Two college students, Halley and Rich, are rock climbing in the West Virginia forest. Rich reaches the top first, and admires the view. Halley starts to struggle and falls, but her climbing line catches her. She calls out for Rich to pull her up the rest of the way, but she doesn't get an answer. Then she sees Rich's hand at the top of the cliff, dripping blood that lands on her face, before his body is thrown off the cliff. The killers then start hauling Halley up by her climbing line, but she cuts her rope and falls. She lands next to Rich's dead body, screams, then runs back towards her car. The trees around her move and three eerie laughs are heard. Just before she reaches her car, Halley trips over a piece of barbed wire and is dragged back into the woods, screaming.
The opening credits feature a montage of newspaper articles and photos about mountain men, genetic mutation caused by inbreeding, and a series of missing person reports, giving a clue to the nature of the killers.
Medical student Chris Flynn (Harrington) is driving through the mountains of West Virginia, on his way to a job interview. Due to a chemical spill in the road ahead, he is forced to take a different route. After receiving unhelpful instructions from an old man at a rundown gas station, Chris decides to take an abandoned dirt road through the woods. He then crashes into a Range Rover stranded in the center of the road.
The car belongs to a group of friends on a hiking trip: Jessie (Dushku), Carly (Emmanuelle Chriqui), her fiance Scott (Jeremy Sisto), Francine (Lindy Booth) and her boyfriend Evan (Kevin Zegers). Their tires were punctured by barbed wire strung across the road. Francine and Evan stay with the cars, while the remainder of the group hikes through the woods to find help.
Francine gets into one of the cars and starts to eat and doesn't notice Evan walking into the woods, investigating a noise he heard there. After a while Francine notices he is missing and goes looking for him. As she ventures further into the woods she finds his sneaker and his severed ear lying on the ground. She screams and stumbles back but is attacked from behind. The killer wraps barbed wire around her mouth, tearing it open.
Meanwhile, the others come across an isolated cabin, filled with odds and ends, and then they discover human body parts in the refrigerator and bathtub. Before they can run, they hear the occupants coming back. They are forced to hide and silently watch as three cannibalistic mountain men, all of them horribly disfigured, enter the house and proceed to butcher and partially eat Francine's body.
After the cannibals fall asleep the teens try to escape but accidentally wake them. The group flee through the woods and hide in a clearing with lots of cars, which they soon realize are the cars of the mutants' victims. Chris makes a diversion and is shot in the leg with a shotgun. Scott then tries to decoy the cannibals away from Chris, allowing the others to steal a truck. Scott runs through the forest and is about to get in the truck with his friends but is shot in the back with an arrow.
The remaining three — Chris, Jessie, and Carly - hit a dead end in the road and have to continue on foot. They climb into an old watchtower and try to use the radio inside to call for help, but get no response. As the cannibals reach the foot of watchtower, someone returns the radio call, alerting the cannibals. The cannibals shoot at the radio through the window, destroying the radio, and laughing maniacally.
After trying to climb the ladder and get into the tower, the cannibals set the watchtower on fire. The three escape by jumping out of a window into a nearby tree. They begin to climb up it but unfortunately, one of the cannibals has climbed into the same tree. Chris and Jessie begin to climb higher up the tree as Carly rests. The cannibal sneaks up behind her and cuts her head in half with an axe.
Chris and Jessie escape the tree and hide in a cave until the next morning, both of them suffering nightmares of the cannibals finding them. Just as they find a road out of the woods, the mountain men find them, push Chris down the hill and capture Jessie and take her back to their cabin.
Chris meets a police officer on the road, but before he can convince the policeman what is happening, the policeman is killed by an arrow from the woods. Chris jumps into the police truck and tries to drive away, but he doesn't have the keys. Chris hides and watches as the cannibal loads the cop's body into the truck and drives it back to the cabin, Chris hitching along by hanging onto the underside.
When they arrive at the cabin, Chris finds Jessie tied up to a bed and gagged with a dog leash. He unties her and they fight with the cannibals, killing them by igniting a set of propane tanks inside, blowing up the house while Chris and Jessie escape into the woods.
The film ends with Chris and Jessie driving the cannibals' truck out of the woods.
The ending credits are interrupted briefly by a scene that shows a sheriff's deputy picking over the remains of the destroyed cabin. Three Finger comes up behind him and kills him with an axe, showing that at least one of them survived. The screen goes black, and you hear the cannibal's insane laughter.