In a hotel, two lawyers named Barry (Bruce Campbell) and Pam (Tiffani Thiessen) are seen entering an elevator. Whilst in the elevator, it jerks to a sudden halt. Pam and Barry start to investigate and come across a corpse in the roof of the lift. Suddenly, they are attacked and then killed by a group of bats.
The next scene cuts to Buck (Robert Patrick), engaging in sexual intercourse, and the audience soon becomes aware that the opening scene was a film Buck has been watching. He then switches channels to view the news and learns that his old "butt buddy", Luther (Duane Whitaker) has escaped from prison. Buck also learns that Texas ranger Otis Lawson (Bo Hopkins) is looking for him. Shortly thereafter Buck receives a visit from Otis and when Otis leaves, Buck gets a call from Luther. Luther who wants to get the old gang back together and arranges to meet Buck at the El Coyote in Mexico. Buck starts rounding up the old team which consists of C.W. Niles (Muse Watson), Jesus Draven (Raymond Cruz) and Ray Bob (Brett Harrelson).
Buck, C.W., Jesus and Ray Bob book a room at the motel, where they wait for Luther. Whilst on his way in his car, Luther hits and kills a bat resulting in his car breaking down. When the car won't start, Luther walks over to a nearby bar, the Titty Twister (the same vampire bar from the previous film... open til dawn). He calls Buck from the bar to tell him about the breakdown. Luther in the meantime is offered a ride to the El Coyote by the bartender Razor Eddie. However, when Razor Eddie (Danny Trejo) finds out about the bat that Luther hit, he turns back. Realizing that the bat was actually his friend Victor (Joe Virzi), Victor and Razor Eddie proceed to attack Luther, resulting in him being turned into a vampire.
Back at the motel, Jesus has sex with Lupe (Maria Checa), a woman he bumped into when he arrived at the motel. After they finish, Jesus sleeps while Lupe grabs a shower. Luther arrive in the windows in the bat form where Lupe is and kills her. Jesus awakes and starts to get dressed. The shower turns off, and he notices a blood puddle seeping from underneath the door of the bathroom. He goes to investigate and attempts to open the door. He kicks open the door from behind Luther and sees the body of Lupe lying lifeless in the bath. Luther then attacks Jesus before he hides in the bathroom. Lupe then reanimates as a vampire and attacks Jesus. He manages to kill Lupe by cutting her head off and then jumps out of the window in order to escape.
Jesus is unsuccessful and is caught and bitten by Luther, transforming into a vampire. Hearing the noise, the owner of the Motel goes to investigate and sees Luther killing Jesus. Panic, she runs to the office and tries to call the police but she is attacked and killed by Luther. While Buck is still in the room watching porn, somebody tries to get in through the locked door. Realizing it is Jesus, Buck opens the door where they find out that Luther has arrived. They then plan the heist which involves the robbery of the Banco Bravos.
The gang drive off to the bank, with Jesus and Luther covering the windows with black paper. Unbeknownst to the gang this is to allow Jesus and Luther to have a place to escape to when the sun rises. Back at the Motel, after receiving the call from the Motel manager, Otis observes the crime scene in the bathroom where Lupe's head in the bath. Upon arriving at the bank, Luther enters the building through the vents and proceeds to kill the security guard on duty and snatches the keys to lets the others in.
Luther and C.W. proceed to the safe where they begin cracking it open. As they try to open the safe they notice the handle on the vault resembles the shape of a cross causing Luther to squeal before quickly covering the handle with a coat. While working with C.W. closely, Luther gets tempted to bite C.W.'s neck. C.W., feeling uncomfortable due to Luther's proximity tells him to back off, before removing Luther's coat from the handle revealing the cross again. Luther is now exposed as a vampire and he bites C.W, turning him into a vampire in the process.
The police arrive at the bank. Buck tries to inform them to escape, but they refuse, being turned themselves into a vampire, except Ray Bob. Buck and Ray Bob leave the bank but are forced back in by the police and SWAT team. With the bank surrounded by police and no escape in sight, Otis arrives and calls the bank. Jesus answers the phone and Otis asks if Luther is there and which Jesus confirms along with Buck. Jesus passes the phone to Buck and Otis asks to speak to the guard. With the guard dead, Buck tells Jesus to pretend to be the guard and tell Otis in Spanish that he is fine.
Otis then tells the SWAT team to enter the bank via the roof. Jesus rips the phone out of Buck's hand and tears it from the wall. Luther and C.W. unlock the vaults, before filling the bags with money. Noticing the SWAT team on the roof Luther has to act and he spots the SWAT team throwing tear gas down the vents. Luther leaps into action and kills them in bat form. Ray Bob, after going to the toilet, is asked by C.W. to help him fill the bags before Luther returns and bites him, turning into a vampire as well. Back in the guard's room, Buck and Jesus are still waiting. Buck takes a lighter from the desk to light his cigarette and notices that Jesus has no reflection in the computer screen.
Luther then enters telling the two to help load the money. Buck holds a gun to Luther, Jesus and C.W. and tells Ray Bob to stand by his side, seeing that his friends are vampires.The group attacks Buck but he prevails and escapes the bank only to be arrested and handcuffed by Otis. Otis sends in the SWAT team to clear out the bank, despite Buck's warning that they are vampires, the group of four vampires brutally murder and feed on the SWAT Teams.
Suddenly, the sun comes up and the vampires try to hide. However, an eclipse takes place and the sun disappears. The four vampires leave the bank and starts to kill the police and SWAT Teams in a full blown blood bath. Once the police have been dispatched with only Buck, Otis, and the Sheriff are left. A face-off between the survivors and the vampires takes place. Just as all of the vampires appear to be defeated, a female police officer who has been turned, attacks the survivors and succeeds in freeing the vampires. Buck responds by killing the female vampire, just as Jesus kills the sheriff.
Jesus then attempts to take the money himself before being caught by Luther. C.W. is then killed by Otis. Jesus is killed by Buck after being thrown onto a car bonnet and is impaled through the heart by a pipe. Luther attacks Otis, as Ray Bob attacks Buck. Seeing that the eclipse is ending, Luther and Ray Bob try to escape, Luther is killed by Buck from behind. Ray Bob then turns back to attack Buck, but he mistimes his attack and the eclipse ends revealing the sun. Ray Bob is killed by the reflection from Buck's sunglasses lens. Buck observes Ray Bob's sizzling skeleton and stumbles across to Otis. Buck and Otis wonder why vampires want money. Otis gives Buck a head start. Buck leaves while the rest of the local police come.