Reality show contestant Kimberly is driving through the West Virginia back country searching for the location of her next project. While driving, she accidentally hits a teenager. She stops to check on him, but the teenager is revealed to be Brother, a cannibal, who bites her lips off. She attempts to escape, but runs into Three-Finger, who splits her in half vertically with an axe. He and Brother drag her halves away.
Former U.S. Marine Colonel Dale Murphy (Henry Rollins) is hosting a survival reality game show in the West Virginia forest, with contestants including: lingerie model Elena Garcia (Crystal Lowe), wisecracking skateboarder Matt Jones also known as Jonesy (Steve Braun), U.S. Marine officer and Iraq veteran Amber Williams (Daniella Alonso), former high school football player Jake Washington (Texas Battle) and a goth Nina Pappas (Erica Leerhsen). After Kimberly does not show up, the show's producer Mara Wilson (Aleksa Palladino) reluctantly takes her place.
When the game starts, Three-Finger kills Neil, one of the television crew. While Dale prepares for the games, Three-Finger and another cannibal Pa, attack and knock him unconscious. Nina and Mara find a log cabin in the woods. Mara enters the cabin to try to find a telephone as Nina follows her. While they look around the house, they hear the occupants return, so they hide in a bedroom. They witness a female cannibal Ma, giving birth to a deformed baby. Her daughter, Sister, spots Nina and Mara in the bedroom, forcing the two to escape through the toilet pit. They run into the woods, but Mara is hit in the head by a thrown axe. Nina searches for the others as the cannibals collect Mara's body.
After showrunner M (Matthew Currie Holmes) and Elena have sex, he returns to the RV while Elena stays by a lake to tan in her underwear. When Elena hears the cannibals, she starts to get dressed as Sister emerges from the bushes and slashes her to death with a machete. While M is in the RV, Ma and Pa hijack it. Pa attacks M and captures him. Meanwhile, Dale manages to escape and battles Three-Finger. After a short fight, Dale shoots Three-Finger with a shotgun.
As Jake, Amber and Jonesy are eating some meat they found, Nina returns and tells her story. When Jake realizes it was Kimberly's leg they had been eating, he, Nina, Amber and Jonesy attempt to escape. Dale finds the old man from the first film in his cabin. The old man tells him how the cannibals' mutations were caused by inbreeding and effluent dumped in the river by the abandoned paper mill. He then reveals that he is their father and attacks Dale. After a brief skirmish, Dale kills the old man by blowing him up with a stick of dynamite. After finding the RV gone, the others run towards the woods and encounter Brother and Sister. After fighting the cannibals, Jake searches for Nina while Amber and Jonesy go for help. Jake rescues Nina from a pit and they jump into the river to escape Sister.
Nina and Jake enter the mill and find a garage full of vehicles stolen from prior victims. They find the RV, and Jake enters it and witnesses M being decapitated on a live feed monitor inside. Nina and Jake attempt to leave but the cannibals, after they had murdered Amber and Jonesy in a trap earlier, capture them. The abandoned mill is revealed to be the mutants' home. Jake is strung up and Nina is strapped to a chair with barbed wire. The mutants eat dinner and force feed Nina.
Dale sneaks into the compound and distracts the cannibals. As the cannibals are searching for him, Dale manages to kill Brother and Sister with dynamite attached to an arrow. He frees Nina and Jake, but is killed by Ma and Pa, who were incensed by the deaths of their children. Nina successfully escapes, but Jake wanders into a room fitted with an enormous tree debarker, where he is attacked by Ma and Pa. Nina returns to the mill and kills Ma and Pa with the debarker. Nina and Jake find Kimberly's abandoned car and drive away. Meanwhile, Three-Finger has survived and is feeding the mutant baby with a finger and a bottle filled with polluted water.