As the movie begins, the concept of the show "Apocalypse: Ultimate Survivalist" is introduced, which is about several contestants surviving in a forest as if though it were the end of the world. One of the contestants, reality-show buff Kimberly is arriving to the location on her car when she accidentally hits "Brother" with it. She stops to check whether he's alright, but when she approaches him, he kisses her and rips off her lips with his mouth. A disturbed Kimberly stumbles backwards and and bumps into "Three Fingers" who chops her in half down the middle with an axe.

Like the original Wrong Turn, it is set in the West Virginia back-country. The show is hosted by retired military commander, Dale Murphy (Rollins), 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, "Three Finger" from the first movie attacks and kills Neil, one of the producers, by slicing off a large portion of his scalp. Afterward, another cannibal called "Pa" punctures Dale's ATV tires with arrows, preventing him from escaping. Dale then throws a knife that hits "Three-Finger" in the chest, who pulls it out and licks the blood from it. Dale turns around only to be knocked out by "Pa".

Later, Michael, Mara's boyfriend, tries to create "sparks" between Elena and Jake, convincing Elena to seduce him. She approaches Jake and attempts this making him feel her breasts, then stripping for him and finally flashing him her tits. Jake doesn't like the fact that Elena is stripping and refuses to engage in any sexual activity because of his morals. He then leaves to look for food in the woods. Elena then turns to Michael and decides to perform a "persuading" blowjob with him while Mara and Nina watch in disgust. Mara is devastated, then she goes with Nina to a cabin in search of a phone. There they witness a cannibal, "Ma", giving birth, and are in turn spotted by "Sister". The girls get out of the cabin through a dug out trench 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 drives off. Nina sets off to find the others.

Down by the lake, Elena has sex with Michael so that he gives her more screen time. He goes back to the RV and Elena stays there to tan in her underwear. "Brother", watching her in the bushes, starts masturbating but is interrupted by "Sister" who is furious and jealous of Elena. "Sister" knocks him over and he sets off an alarm which Elena hears. "Sister" runs out of the bushes towards Elena, who trips and falls into the lake. "Sister" slashes her across the back with a machete repeatedly, killing her. She stops hacking at the body when "Brother" comes out of the bushes. "Sister" suddenly becomes passive and lovingly caresses "Brother"'s face. She then kisses him.

Back at the RV, Michael is stabbed with an arrow, taken to the cannibals' home, and later decapitated. As Three-Finger tortures Dale, who is suspended upside-down, he uses a moment to his advantage, manages to escape, and shoots the mutant with a shotgun.

Jake finds Amber and Jonesy at a barbecue pit. As they eat the discovered meat, a crazed Nina races up and tells her story. Jake then realizes it was Kimberly's leg that they had been eating after spotting her signature snake tattoo. As they run, Dale finds "The Old Man" (same old man and actor from 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 by blowing him up with a stick of dynamite.

After Amber, Jonesy, Jake, and Nina notice that the RV is gone, they run towards the woods and hear moaning sounds. They believe that "Brother" is raping Elena. Jake gets up to intervene, and it is revealed that the woman is actually "Sister" wearing Elena's hair (obviously scalped from Elena's head). Nina runs, horrified, and falls into a trap set by the cannibals. Amber, Jonesy and Jake fight the cannibals and "Brother" falls and punctures his head on a rock. Amber, Jonesy, and Jake look for Nina. Jake decides to look for her while Amber and Jonesy go for Help. Jake finds Nina in the trap hole and runs towards the river, where "Sister" finds them and shoots at them as they jump to the river. After a chase, Amber and Jonesy get caught in a trap and are soon killed with a single dual headshot arrow. Meanwhile, Nina and Jake make it to the mill. They walk through the first gate and Nina sees a tank with a toxic symbol. Jake and Nina then enter the mill and search around. They hear a truck and make their way to a view of a garage filled with stolen empty cars. They hear Michael screaming and Jake arms himself whilst Nina waits outside the RV. Jake enters the RV and realizes that Michael's screams weren't coming from the RV, but from somewhere close. Jake then watches via live feed Michael being decapitated. As Nina waits outside the van, she hears a giggle and "Sister" appears. Nina is then dragged away. Jake screams to her, but when he turns around, "Pa" is standing there. Jake hits "Pa" with a monkey wrench, but "Pa" shakes it off and easily overpowers him.

The abandoned mill is revealed to be the mutant's home, and Dale managed to sneak into the compound. The family of mutants appear to function and take part in certain activities like any normal family such as watching television together and saying grace before eating. Jake is held captive while Nina, who was originally caged up but after antagonising "Sister", is strapped to a chair lined with barbed wire at the table. During the mutants' "dinner" they begin to force-feed Nina with parts of Michael's flesh dipped in the mutagenous material as well as rubbing it on her skin, so as so turn her into one of their own.

While sneaking, Dale catches in a noisy trap, alerting the family who soon chase him. He manages to kill "Brother" and "Sister" with dynamite stuck to an arrow and goes to Nina and Jake. He frees Nina and, while helping Jake, is shot in the back with an arrow and is then killed by a razor-wire chain thrown around his throat. Nina successfully escapes, however Jake wanders into a room where an enormous tree de-barker is kept, and soon gets into a fight with "Pa". Nina returns to the mill and meets up with Jake, who kills "Ma" and "Pa" with Nina by pushing them towards the de-barker while she releases a log that knocks them into the de-barker, subjecting them to the same fate they ultimately put all their victims through. They then find Kimberly's abandoned car and drive away to safety.

As the film ends, the still alive Three-Finger feeds the newborn mutant baby Mara's finger and a bottle filled with a greenish chemical waste. His laugh is heard over the end credits.