The film opens in May 1978 with newspaper clippings about missing people and a summary of how they were found. Police officials raided the Firefly house and found body parts in the refrigerator, as well as furniture made out of human limbs. They also found enough evidence and corpses in the basement to put the Firefly body count at 75 people, maybe more. The family would forever be known by the media as "The Devil's Rejects".....
On an early morning, Tiny (Matthew McGrory) is seen dragging a naked mutilated female body through the woods. He is on his way to the Firefly house when he spots numerous police vehicles making their way down to the house as well. Tiny lifts up his burlap sack covering his burnt face and looks at the swarm of police as they approach the house. Tiny remains unseen in the forest.
The police arrive and park in front of the Firefly house. The police are led by Sheriff John Quincy Wydell (William Forsythe), brother of Lieutenant George Wydell (Tom Towles) who was killed by the Firefly family (in the first movie, "House of 1000 Corpses"). The police strap on bullet proof vests and ready their guns. Officer Ray Dobson (Dave Sheridan) asks Sheriff Wydell if he thinks they will die today. Wydell tells him: "dying ain't an option". He pumps his shotgun and gets ready to talk through a speaker box. Inside the house, Otis (Bill Moseley) is sleeping next to a naked female corpse, Baby (Sheri Moon) is fast asleep in her room, and Mother Firefly (Leslie Easterbrook) sleeps in her bedroom. They are all awakened when Wydell orders them to come out peacefully because the police have the house surrounded. Otis looks through a window and sees all the cops. He puts on shirt and jeans, picks up his pistol, then walks downstairs. Baby gets dressed and grabs her gun, and heads downstairs with Mother Firefly. Rufus Jr. (Tyler Mane) is already at the bottom of the stairs in full metal body armor and tells them that they are completely surrounded. The Firefly brood ask about Tiny and Mother Firefly says he left last night and hasn't come back. Otis and Rufus position themselves at the front of the house while Mother Firefly and Baby position themselves in the back by the kitchen. Mother Firefly is crying, and says she remembers how Baby looked like an angel when she was born. Baby and Mother Firefly say "I love you" as they put on their metal masks. Otis dons his metal mask, which has a skull painted on it, and readies to fire on the police.
Wydell and the cops open fire on the Firefly household. The family members inside take cover and then return fire. Otis and Rufus fire machine guns while Baby and Mother Firefly fire pistols. They kill a couple of cops, but are fired upon heavily again by the law enforcement outside. During this shootout, Otis shoots Wydell in the chest, but his bullet proof vest keeps him alive. This enrages Wydell even further and he walks slowly towards the house pumping shells from his shotgun. Eventually, he orders the officers to cease fire and throw in tear gas. Wydell kicks in the door to the gas-filled house and is followed by the other officers (all of whom are wearing gas masks). Suddenly, Otis and the family come out of their hiding places and again open fire. The cops around Wydell get hit but he doesn't. Otis, Baby, and Mother Firefly make their way to the kitchen entrance while the police unload their guns into Rufus' body armor. Rufus eventually dies from all the bullet hits. Mother Firefly sees that her son is dead and goes to his side while Baby and Otis go through a secret tunnel in the house. Wydell orders Mother Firefly to drop her gun, but she points it to her own head and says "you'll never get me". She pulls the trigger, but the gun is out of bullets. Wydell tells her "it looks like it's not going to be that easy".
As the opening credits roll we see Otis and Baby running through the secret tunnel while their kidnap victims scream at them. The tunnel leads to a sewer, and Otis and Baby escape through it. They run through a nearby field with their weapons in hand as the police enter the house and discover all of their victims. Mother Firefly is taken in handcuffs to the police station. A nurse (Mary Woronov) drives by and sees Baby lying in the road. and gets out of her car to make sure Baby's alright. Baby jumps the woman and holds her down and Otis pops out and stabs the nurse to death. They steal her car and drive off. The police, upon further search of the house, come across several notebooks and pictures of all the people the Fireflys have killed. They notice that Captain Spaulding (Sid Haig) is in a lot of the pictures with various dead people, smiling while showing off his bloody hands. Wydell recognizes Spaulding and orders his men to find him.
Meanwhile, we see Spaulding having wild, rough sex with a prostitute (Ginger Lynn Allen). After they are done, Spaulding calls her a whore. She draws a gun on him and says she is not a whore to which Spaulding replies "I call them as I see them". She cocks the gun to blow his brains out and Spaulding says he's just joking around with her. She laughs and blows his brains out. Spaulding wakes up (it was all a dream) and we see he is sleeping with an unattractive husky woman. She asks him if he had a bad dream. Spaulding looks at the woman he just had sex with and says "it was 50/50". They get out of bed and watch Spaulding's new TV commercial advertising his new monkey attraction. Spaulding's pissed when his commercial is interrupted by a news bulletin. He's even more pissed, and worried, when the news clip shows the raid on the Fireflys who the media have dubbed "The Devil's Rejects." When Baby calls Spaulding we realize he's her father. Baby explains what happened and they agree to meet at the motel they're supposed to meet at in case of an emergency. We see Baby get in the car with Otis and drive away while Spaulding leaves his house and drives to the motel.
Back at the police station, Wydell and several officers interrogate Mother Firefly about the whereabouts of the other family members. She refuses to rat out her own family and says that the cops just want to have sex with her (she used to be a prostitute). Wydell shows her notebooks and pictures of her victims, but she is unmoved. Mother Firefly then gets some pictures from a notebook and says that she never knew exactly where to put them. She shows the photos to Wydell and they turn out to be his dead brother. She pieces together that this Wydell is related to the one she'd killed and insults them both. Wydell loses it and back-hands her face. He grabs her throat and says "I'm going to kill your whole fucking family!". Officer Dodson and the other officers pull Wydell from her and they all leave. As they do, Mother Firefly loses it as well and spouts insults, while saying that her family will kill Wydell.
Meanwhile, we cut to a ranch which is called Charlie's Frontier Fun Town, a brothel, which is run by Charlie Altamont (Ken Foree). His assistant Clevon (Michael Berryman) cleans the place mostly. Charlie's counting money and he's surprised by how little cash he's got. Candy (Elizabeth Daily) says the only customer she got was a farmer who only wanted a hand job. Charlie says they've got to think of new ways to attract more customers. Candy says that she has an idea: they could do a Star Wars theme and she'd dress up like Princess Leia. She figures lots of geeks will want to have sex with Princess Leia, and Clevon says he definitely would. Charlie says he will keep on brainstorming. The phone rings, and it's Spaulding calling from a payphone. We find out Charlie and Spauldding, who gives him a rundown of the situation, are adopted brothers. Charlie doesn't want the Fireflys coming to his place but Spaulding's response is to hang up the phone.
Otis and Baby arrive at the agreed upon motel but Spaulding's not there yet. Otis calls him a "dumb old bitch" then Baby and Otis exchange insults with one another. He orders her to get a room to chill out in until Spaulding arrives. Baby looks around and comes across a traveling band called "Banjo & Sullivan". Adam Banjo (Lew Temple), his wife Wendy Banjo (Kate Norby), Roy Sullivan (Geoffrey Lewis), and their roadie Jimmy (Brian Posehn) are all making fun of Roy's wife Gloria (Priscilla Barnes) because her breasts popped out while she was riding a mechanical bull the night before. The Banjo's and Gloria get settled in Room 2, while Roy and Jimmy go out to get ice. On the way to the ice machine, Jimmy says that he thinks he could be a good clown and do a bull act. Roy thinks that Jimmy can do something better and sends him to a nearby gas station to get beef jerky. Roy is alone filling up an ice bucket when Baby runs into him. She pretends she's looking for her cat. Baby flirts with Roy who obviously likes it. Baby asks to go to his room so they "can have some fun". Roy says that he can't, as his wife is in his room. Baby then tells him to take her to his room or else her half-brother (Otis) will kill him. Otis appears with his gun in hand and they all proceed to walk to Room 2.
Wendy is showering while Gloria watches a talk show about satanic stuff. She tells Adam to change the channel. Adam does and hears some knocking at the door. Adam opens the door and Otis shoves him onto the bed. As Roy enters the room he too is shoved onto the bed. Otis hears the shower and bursts into the bathroom. He drags the nude Wendy out of the bathroom and pushes her too onto the bed. Adam covers her up with a blanket and a flannel shirt. After exchanging insults with Baby, Otis asks if there is anyone else with them. Roy says "no" just as Jimmy comes back from the gas station and knocks on the door. Otis orders everyone stay cool and be quiet. Baby answers the door and lets Jimmy in. She shoves him onto the floor and Otis shoots him in the forehead, killing him. Everyone screams, and Adam vomits over Wendy and the bed. Otis gets really pissed off at Roy, saying he can't trust him.
Meanwhile, Spaulding's red truck runs out of gas so he pulls it off onto the shoulder and wonders what to do next. He sees a woman (P.J. Soles) and her young boy coming out of a convenience store nearby. He approaches them and tells them that he needs to take their car "on account of top secret clown business". He laughs with the woman, and she then asks what he wants. Spaulding asks back "did I stutter, bitch?". The woman orders her son to get into the car and to lock the door (he does). She walks around to the driver's side and tries to open the door, but Spaulding punches her in the face and gets in. The boy is clearly scared, and Spaulding asks him why he doesn't like clowns. The boy doesn't answer. Spaulding tells him that he's going to come back, and if the boy doesn't have a good answer to why he doesn't like clowns, he's going to kill his entire family. He orders the crying boy out of the car. Spaulding drives off to meet his kids (Otis and Baby).
Back at the motel, Baby dances in front of Roy. Otis asks him if he likes what he sees, but Roy says no. Otis asks him if he is queer or something. Roy says he is a married man. Otis orders Gloria to get up and to take off all her clothes so he can see what Roy is attracted to. Gloria takes off her pants and is in her bra and underwear. Otis gets up and runs his gun up and down her body. He eventually gets to the point where he puts his gun down the front side of Gloria's underwear and forces her to fellate him. After he's through, he calls her disgusting and shoves her back onto the bed. He then orders Adam and Roy to take a road trip with him. They leave in the "Banjo & Sullivan" van while Baby stays in the room to keep an eye on Gloria and Wendy.
Otis has Adam drive to the desert. Once they reach their destination (which looks like a junkyard), Otis orders Roy and Adam out of the van. They have to walk the rest of the way. Adam wants to know exactly where he is taking them. Otis honestly tells them that they are going to dig up a crate of weapons that he buried some time ago and then implies that he is going to kill them afterwards. Roy and Adam stop walking to plead with Otis to spare their lives. Otis taunts Adam by asking if Wendy gets off when he vomits on her. Adam lunges at Otis, but he shoves him aside and aims his gun at Roy's head. Adam then grabs a piece of wood and hits Otis in the head with it. Adam hits Otis with the wood a couple of more times, but Otis won't go down that easy. However, Otis loses his gun and Roy tries to retrieve it. Otis jumps on top of Roy and struggles with him. Adam jumps on top of Otis and hits him a couple of times. Otis then takes out his very sharp hunting knife and rams it into Adam's leg. Otis continues to struggle with Roy over the gun. Adam rips the knife out of his leg and tries to stab Otis. Otis forces Roy to pull the trigger on the gun, and he makes Roy shoot Adam in the neck. Adam goes down. Otis snatches the gun away and proceeds to pistol whip Roy. After he's done, he picks up the piece of wood that Adam used on him and hits Roy in the crotch with it. Otis walks over to the bleeding Adam, who begs Otis to stop. But the angry and bruised Otis says "I haven't even begun!" He shows him what happens to men who try to be heroes: Otis grabs the piece of wood and smashes Roy's skull, killing him. He then walks over to Adam and tells him that he has something else planned for him. Otis begins to slash up Adam's face with his knife.
Back at the motel, Baby watches a singer on TV. Gloria hums along with the music but Baby tells her to shut up. Wendy has to go to the bathroom. Baby says that she could care less about where Wendy pees. If Wendy is to go to the bathroom, Baby wants something in return: she wants Wendy to hit Gloria. Wendy is hesitant, but Gloria assures her it is okay. Wendy lightly slaps Gloria, but Baby is not happy. Wendy slaps Gloria harder, but Baby is still not happy. Wendy slaps Gloria the hardest she can. Baby orders Wendy to kiss her and say "Baby, I'm having a great time". Wendy kisses Baby on the cheek and repeats the line. Wendy goes to the bathroom and Baby tells her to make it quick. Once in the bathroom, Wendy frantically looks for a way out. She smashes the window with the toilet lid and screams for help. Baby gets up and gets up to kill Wendy when Gloria grabs Baby's gun and points it at her. Baby asks her why she would do that, and we see Baby hiding a big knife behind her back. Gloria says that she will pull the trigger. She then yells to Wendy that everything is fine, and she can come out of the bathroom. Baby then throws her knife into Gloria's chest. Gloria drops to her knees and pulls out the long knife from her chest. Baby pulls down her pants and playfully tells her to "shoot her bottom off". Gloria, near death, raises the gun at Baby's butt and pulls the trigger. Nothing happens. Baby laughs and says the gun isn't loaded. Wendy comes out of the bathroom to find Gloria dying. She pushes Baby out of her way and runs outside. Gloria dies.
Wendy bangs on all the doors of the motels creaming for help but nobody will answer. As she runs to the pool area she sees a man she thinks will help.The man turns out to be Spaulding. Baby catches up to Wendy and tells her father that she almost got away. As Wendy realizes who her "savior" is, he head-butts her unconscious.They drag her back to the motel room gagging her and tying her to the bed post. Spaulding asks where Otis is and Baby tells him Otis went to their secret stash to get the guns. Spaulding says Otis better not mess it up as Otis bursts into the room scaring the two. Otis has cut Adam's face off and is wearing it as a mask. Otis and Spaulding insult each other but Baby tells them to quit. They discuss what to do with Wendy. Spaulding suggests leaving her behind for the maid in the morning, but Otis says he has something better in mind. The scene ends with Otis kissing Wendy with Adam's face.
The next morning, a motel maid finds nobody in Room 2 so she enters to find the place a mess. She opens the bathroom door to find the butchered remains of Jimmy and Gloria in the bathtub. The words, "The Devil's Rejects" and "fuck you" are written all over the wall with blood. As she screams she wakes Wendy who is tied to the front door. We see Otis has strapped Adam's face onto hers. Wendy breaks free and falls on top of the maid. The maid freaks out and runs away. Wendy wildly chases the maid in hope that she will help her. When she can't catch up to her, Wendy runs into the middle of the road and tries to wave down a car but wearing her husband's face, no one will slow down for her. A big truck runs over Wendy and she is killed.
Sheriff Wydell and the police are called to the scene. Wendy's body parts and brains are splattered all over the road. The police realize, as the local sheriff (Steve Railsback) confirmed, that the scene is a gory mess. Wydell orders a deputy to clean her brains off of the pavement and then goes to the maid and shows her pictures of Spaulding, Otis, and Baby. He asks her if she has seen any of them, but she says 'no'. Wydell is called away because he has some visitors: a pair of bounty hunters who call themselves "the Unholy Two". These two men are Rondo (Danny Trejo) and Billy Ray Snapper (Diamond Dallas Page). Wydell gives them the mugshots of the three fugitives and orders them to find Spaulding, Otis, and Baby.
Back at the police station, as the police search the police records they come to the realization that the Firefly family names are taken from characters in the movies of Groucho Marx and the Marx brothers. Wydell and the police research the names of characters in Groucho movies.They call in a "film expert" to help them, but he turns out to be useless. Wydell then gets a call from the Unholy Two who tell him that they discovered Charlie Altamont uses a Groucho character name as an alias. Wydell figures out that the Firefly's are headed to Charlie's place.
As Otis drives Spaulding and Baby in the stolen van, Spaulding tells him to drive to Charlie's brothel. Otis doesn't trust Charlie, but Spaulding orders him to drive there anyway. Baby sees a sign for ice cream and wants Otis to stop. Otis explains he won't stop, because those 20 seconds they spend getting ice cream could wind up being dangerous to his health. Spaulding and Baby proceed to annoy Otis by chanting they want "rutti fucking tutti". Otis tells them "there is no ice cream in your future". The next scene we see Spaulding and Baby eating ice cream, and Otis irritated that he actually caved in. Baby offers Otis some of her ice cream, but he refuses. As they listen to music Baby gets ice cream on Otis' beard and they all laugh about it.
Meanwhile, Wydell is at the Firefly house. As he goes through the basement he hears what he thinks is Spaulding's voice and sees the top of his head. But when Wydell sees who it really is he freaks out; it is his dead brother George. Wydell asks George what he's doing down there, and George tells him that it is his home now. He doesn't have a choice in the matter, and he is stuck there until the Fireflys die. George urges Wydell to step "over the line" and kill all of them for him. Wydell suddenly wakes up and we realize it was a dream.
Later that night, he goes to visit Mother Firefly in the jail house. He tells the guards to go home leaving him alone with Mother. She taunts Wydell telling him he just can't resist having sex with her. Wydell's response is to stab Mother Firefly twice in the chest. She is dead. Pulling the knife from her chest he leaves it on the table and walks away.
That evening, Otis, Baby, and Spaulding arrive at Charlie's Frontier Fun Town. Charlie walks outside with a shotgun and orders them to put their hands in the air. As they comply Otis becomes pissed off that they came all the way out there just to get held at gun-point. Charlie shoots Spaulding in the face at which time we realize Charlie's holding a squirt gun. They hug each other and catch up on old times. Charlie, Otis, Spaulding, and Baby proceed to party and get drunk with Charlie's prostitutes (with the occasional weed). While at the same time Wydell has gone completely berserk and is talking to himself in the mirror. He vows to kill all of them for his brother.
The next morning, Charlie and Clevon leave to get chickens for dinner. Charlie tells Clevon that Spaulding makes the best fried chicken. They drive until they find a guy who is selling chickens. The guy asks them if they have sex with chickens. Charlie and Clevon are both offended by this and the guy tells them he's only asking because it looks like they, especially Clevon, have a lot of sexual tension locked up inside. Charlie and Clevon especially are weirded out when the guy says when you cut off the head of a chicken and stick your penis inside, it feels like a vagina. Charlie buys a couple of chickens (for eating) and he and Clevon leave.However, they don't get very far because Wydell's blocking the road with his truck. Charlie gets out of his car and when he walks up to Wydell's truck Wydell uses the truck door to hurt Charlie's fingers. Wydell then orders him to keep Spaulding and the two others pre-occupied at his place until midnight. If he refuses, Charlie will be killed. Wydell leaves, and Charlie is left with quite a dilemma.
Wydell meets up with Billy Ray Snapper and Rondo at Snapper's trailer home. He tells them the Fireflys will be at Charlie's place at midnight. He warns Snapper and Rondo not to mess up tonight and explains he doesn't care what condition the Fireflys are in but wants them alive enough to feel the same pain their victims felt. The Unholy Two tell Wydell he's very sick and twisted and Wydell's only response is again to tell them not to mess up..
That night, Charlie and Spaulding snort cocaine and we see Charlie take the coke as he leaves to go to the bathroom while Spaulding puffs away on a joint. Otis is fooling around with Candy, and Baby is taking a sponge bath and talking to a prostitute named Cassey (Deborah Van Valkenburgh). Cassey goes to the fridge to get herself and Baby some cold beers. Rondo sneaks up behind her then covers her mouth and violently slits her throat. Billy Ray Snapper scratches the record and Otis realizes that they have been caught. Rondo orders Baby at gunpoint to get up and Baby (completely naked) goes to get clothes. Candy grabs Otis' gun and tries to shoot Billy, but he shoots her dead with a bullet to the forehead. Otis lunges at Billy who promptly chucks Otis out the window. Wydell arrives where Spaulding is hiding and throws back a shot of liquor before suprising the clown. Spaulding insults him and his brother, so Wydell shoots Spaulding in the belly. The Fireflys then discover Charlie betrayed them. Wydell herds Spaulding, Otis, and Baby into the back of his police truck and tells Rondo and Billy that their services are no longer needed. The Unholy Two then drive away as Wydell drives in the opposite direction toward the Firefly house.
The three killers sit tied to chairs in the basement listening to Wydell talk about how his family has always been demon slayers. Wydell kicks Otis in the crotch and orders him to stay awake. He picks up a picture of a missing girl and shows Otis a picture of the girl's corpse when she was found in the house. Otis says that the girl's still sex worthy. Wydell staples the pictures to Otis' chest. Wydell walks over to Baby and staples her with pictures of a girl she killed. Spaulding insults Wydell who proceeds to beat Spaulding almost to death with a metal pipe. Wydell punches Otis and Baby as he continues to torture them. Wydell continues to get shitfaced drunk and nails Otis' hands to the chair's armrests. Wydell unties Baby and tells her to run. He then splashes gasoline all over the floor and lights it on fire, leaving Otis and Spaulding to burn to death.
Baby runs outside through the place where the family kept cows. Wydell grabs an axe and says Baby is like a rabbit, and she should run like a rabbit. He chases Baby around the farm. She hides in a barn and runs into Charlie. Baby's pissed at him for giving them up but Charlie proceeds to explain he came to get them out of there. She says Otis and Spaulding are tied up in the house which is currently in flames. Charlie puts Baby in his car saying he'll get the others. As he leaves for the house Wydell shows up and plunges an axe into Charlie's throat. He rips out the axe and hits him again to kill him. Wydell chases Baby out of the car. As Baby tries to flee she is thrown to the ground when Wydell fires his gun and hits her in her lower left leg. Wydell, now completely deranged, begins to choke her to death with his bare hands. A figure suddenly appears behind Wydell and lifts him off the ground. It's Tiny, who then wraps his arms around Wydell and with super strength kills Wydell by breaking his neck. Baby tells Tiny to save the others from the burning house. Tiny goes inside to the basement where he rips the nails out of Otis' hands freeing both him and Spaulding. They all escape the house.
In the front seat of Charlie's car, Otis gets behind the wheel while his step father Spaulding (whom he addresses as 'Cutter') and half-sister Baby climb into the back seat. Otis asks Tiny, "are you sure you want to do this?" Tiny nods. Otis says they will come back for him. Otis and the remaining Fireflys drive away and we see Tiny slowly walking into the burning house which proceeds to blow up with Tiny inside.
As dawn breaks, Otis is driving through the desert mountains with Baby and Spaulding asleep in the back seat, all of them thinking about the good times they have had together. Otis suddenly stops the car. A look of disappointment, fear, and sorrow comes across his face. We see just further ahead on that road is a HUGE police blockade. The officer in charge of the barricade is Ray Dobson, the young officer seen with Wydell in the opening raid and at Wydell's side through most of the movie. Otis tearfully wakes up Spaulding and Baby in the back seat. They see they are not going to make it. Baby stands up in the back seat after Otis gives her a gun, Spaulding takes the shotgun, and leans out the right-side of the car. With a gun in his left hand Otis drives with his right as they speed firing toward the police. Although they hit a few police they are seriously outnumbered. Wounded by police fire Otis continues driving and he, Baby and Spaulding continue shooting at the police, all three of them taking multiple hits. In their final act of demented glory, the Fireflys ram their car into the roadblock and their mad lives are ended in a hailstorm of police bullets.