One year after the events of the first film, ''Wrong Turn 2'' opens with a contestant Kimberly, a spoiled celebrity who's running late for her appearance on a ''Survivor''-like reality television show. Losing her bearings in the mountains of West Virginia and while complaining to her agent on the phone, she accidentally hits someone with her car. Visibly shaken, she goes to help him, unaware that the victim is a mutated cannibal. After attempting to help, "Brother" bites her lips off while the surviving cannibal from the first film, Three-Finger, cuts her vertically in half with an axe as she stumbles back to her car. The two cannibals each drag half of her body away.
As the opening titles roll, we meet with five strangers, Nina, the goth, loner girl, Jake, the athletic, kind hearted guy, Jonesy, the goofy joker, Elena, the token slut and Amber, the tough military girl. They are competing in the reality show called "Apocalypse: Ultimate survivalist" with a theme that it takes place at the end of the world. The show is hosted by retired military commander, Dale Murphy, who makes them give up all outside communication before starting. After Kimberly doesn't show up, the show's producer Mara steps into her place. As they move into the forest, the surviving cannibal from the first movie attacks and kills one of the show's producers. He then knocks out and captures Dale.
Mara, after catching her boyfriend Michael cheating on her with contestant Elena, goes with Nina to a cabin in search of a phone. There, they witness a cannibal "Ma" giving birth, and are, in turn, spotted. The girls get out of the cabin as "Sister" kicks down the door. The two run away into the woods with the cannibals chasing them. During the pursuit, Mara is hit in the head with an axe and killed as Nina hides. One of the cannibals, "Pa", looks for her but doesn't find her. The other cannibals drive up with Mara tied to the hood of their truck and the cannibal gets in and drive off. Nina sets off to find the others. Down by the lake, M goes back to the RV and Elena stays there to tan. A cannibal watching her in the bushes starts masturbating but is interrupted by Sister who is furious and jelous of Elena. Sister knocks him over and he sets off an alarm. Elena hears it and gets up and starts to get dressed. Sister runs out of the bushes towards Elena who trips and falls into the lake and Sister slashes her back with a knife relentlessly, killing her. She only stops when Brother comes out of the bush and they start kissing. Back at the RV, Michael is stabbed with an arrow, taken to the cannibals' home, and later decapitated. As Three-Finger tortures Dale, he uses a moment to his advantage, manages to escape, and shoots the mutant with a shotgun.
Amber and Jonesy find Jake at a barbecue pit. As they eat the discovered meat, a crazed Nina races up and tells her story. Jonesy then realizes it has been Kimberly's leg that they've been eating after spotting her signature snake tattoo. As they run, Dale finds "The Old Man" (from the previous movie) in his cabin. Dale tells him about the cannibals and soon realizes the man is their un-mutated father. After a brief skirmish, Dale kills the old man.
Amber and Jonesy are soon after killed with arrows, while Nina and Jake get trapped, captured and brought back to the mutant's home, after discovering an abandoned mill filled with stolen, empty cars. As they torture Nina at their dinner table, feeding her with human flesh, an enraged Dale enters their compound, kills several of them, and is then killed by a spool of barbed wire that gets wrapped around his throat. Nina successfully escapes, however Jake wanders into a room where an enormous meat grinder is kept, and soon gets into a fight with Pa. Realizing she has to help him, Nina returns to the mill and along Jake kills what they believe are the last mutants by pushing them into the grinder. They then find Kimberly's abandoned sports car and drive away to safety.
As the film ends, the still alive Three-Finger feeds the newborn mutant baby Splooge Mara's finger and a bottle. His laugh is heard over the end credits.