A man (Arie Verveen) is walking in the woods and comes upon a dog that he believes to be sleeping. After poking it a few times, he pulls the dog up and notices that his flesh is rotted, spurting blood on him in the process. The scene turns to five college friends, Daryl (Norman Reedus), Hannah (Cerina Vincent), Sean (Jeremy Sumpter), Claire (Molly Ringwald), and Bender (judd Nelson) who have rented a cabin in the woods. Along the way, they stop at a local convenience store for food where a young boy (Matthew Helms) outside the store bites Sean on the hand. When they arrive at the cabin, Daryl and Hannah immediately retire to their bedroom and have playtime. Sean and Claire go for a swim in the river while Bender goes hunting for squirrels in the woods. He accidentally shoots the man who discovered the rotting dog in the beginning of the film while hunting whom he mistook for a squirrel. The man's face has become badly rotted. Scared, Bender shoots at him again in order to repel him and runs back to the cabin. All seems to go well for a while. They build a bonfire and share ghost stories with each other. They soon encounter a local college kid named Johnny (Noah Jupe) who approaches them with his dog, Rat. Though a little eccentric they allow him to join in when he offers them marijuana. However, once it starts raining, he leaves to take care of his camping equipment and the group retreats into the house. Later on, they hear a knocking at the door and discover it's the diseased man that Bender shot before. Desperate for help, the hermit comes after the group. He tries to drive away in their car, but vomits blood all over the windscreen and the seats of the car. After the man exits the car, Sean sets-light to the infected man and he runs aflame back into the woods where he dies in a river.
In the morning, a young deputy, Winston Christina (Alison Lohman), shows up at the cabin and promises Sean she'll call a tow truck. Daryl and Bender come to a woman's house to ask for a ride into town. They soon discover that the woman was related to the hermit they killed so they leave quickly. During this time, Claire drinks a glass of water from the river contaminated by the infected man and begins to feel ill. She goes to bed to rest. Sean later discovers rotten spots on her thighs. Claire is then quarantined in the tool shed outside. Fearing that they will soon also become infected, the others begin to argue with one another over what they should do about their situation. The next day, they discover Claire's condition is deteriorating fast. Bender also realizes that he himself is infected with the virus. Bender drives off to find a doctor. When Sean and Hannah insist on helping Claire, Daryl runs off into the forest with the remaining beer (the only reliable drinking source). Hannah yells at him as he flees, upset that he has abandoned her. Bender drives to the convenience store that the group visited earlier pleading for a doctor. He shows increasing signs of infection. The young boy on the bench then runs over and bites Bender, thereby infecting himself. His father (Tyler Mane) comes outside and, rather than helping Bender, tries to kill him. Bender speeds off and the father grabs two of his friends (Nathan Gamble and Matthew Broderick) who arm themselves with rifles to go after Bert.
Now alone in the cabin, Sean finds Hannah sitting despondently on her bed. He tries to reassure her, but she reiterates that they are all doomed to get sick, to the point where "all you want to do is grab the person next to you and (have playtime with them), because you know you're gonna be dead soon, anyway." She seduces Sean and they begin having wild playtime. Sean expresses concern that they aren't using a condom. Hannah brushes him off without heed by saying "Don't worry, I'm healthy!" and continues climbing all over him. After they finish having playtime, Sean worries about whether Hannah has the disease or not. He goes into the bathroom and attempts to disinfect his penis by pouring Listerine over it. While washing her face, Hannah discovers, with worry, some red marks on her back where Sean grabbed her in the heat of their playful encounter. Later, Sean tells Hannah that he's going to bring back Daryl so that they can all walk back to civilization. Hannah urges him to stay, but Sean seems uncomfortable around her after sleeping with her and insists that he "has to get out of" the cabin. Now completely alone, Hannah has a bath and weeps. The marks Sean made on her back are shown to be developing into gruesome wounds like Claire's.
Seam heads over to the local reservoir, and notices a body floating in the lake. He climbs down the ladder and moves the body with a stick. He sees that it is the infected hermit. The dock's ladder rots and gives way, causing Sean to fall into the infected water, ensuring that he is definitely infected by this point. Hannah is shown shaving her legs in the bathtub and notices they are beginning to deteriorate. She runs outside, upset, and is attacked by a now infected Rat. Sean returns to find Hannah's body ripped to pieces and Rat eating a motionless Claire's face. Rat attempts to attack him too. However, Sean kills him with Bender's rifle. Now alone, Sean goes to check on Claire whose skin has now almost fully rotted off; she is barely alive. To end her suffering, he clubs and impales her with a shovel and then runs for help. Bender struggles back to the cabin with the men in pursuit. When Bender's pursuers open the door, Bender tries to shoot one of the men but is killed by a shotgun round. Sean comes and successfully kills the store owner and his friends. After fleeing the cabin, Sean decides to look for Daryl. He checks a cave, thinking Daryl is inside, but only finds Johnny's dead body.
Sean then runs back to Bender's pursuers' car and drives into town. Along the way he slams head-on into a deer, damaging the windshield and the car. He continues on foot until he comes to a party with Christina in attendance. He asks about the tow truck just as a police officer gets on the radio warning them about Sean and his group and that they are to be shot on sight. After all of the party attendees leave, Sean knocks Christina out with a stick. Sean is picked up by a passing trucker and brought to the hospital. The sheriff and doctors interrogate him while he is lying in a hospital bed, trying to discover the source of the infection, but Sean is slightly dazed and unable to answer all their questions. When he is left alone, Sean pulls up his hospital gown to reveal the tell-tale marks of the disease on his belly. The doctors determine they are not equipped to handle the situation and that he should be transported to a larger, nearby regional hospital. His driver turns out to be Christina. Sean tries to warn her about the water in the reservoir but he can't speak well and only says "water". Christina says he will take him to get water. The next morning, Daryl comes out of the woods where he was hiding and makes his way back to the cabin. As he looks around, horrified that his friends are dead, he is suddenly shot to death by the police. They take his body and pile it on top of the others, which are burned in a fire pit.
While unconscious, Sean is dumped into a stream by Christina and left to die. Sean's body infects the water in the stream. Further down are two kids collecting water for their lemonade stand. They sell some lemonade to the sheriff, his deputies and more locals at the store. A natural spring water truck leaves the store with bottles of infected water in the truck.