A man walks through the forest and encounters a dog, initially believing it to be sleeping. However, upon nudging it, he realizes the dog is dead and its decayed flesh splatters blood on him. Meanwhile, five college friends—Jeff, Marcy, Paul, Karen, and Bert—are traveling through rural Alabama in a van, on their way to a rented cabin in the woods. They make a stop at a local convenience store, where a young boy outside unexpectedly bites Paul on the hand. The locals observe the group with a mix of suspicion and contempt.
Upon arriving at the cabin, Jeff and Marcy quickly retreat to their bedroom to have sex. Meanwhile, Paul and Karen take a swim in the nearby lake, while Bert decides to hunt for squirrels in the woods. However, in a tragic mistake, Bert accidentally shoots the man who discovered the dead dog earlier, mistaking him for a squirrel due to the state of his rotting face. Terrified, Bert shoots at the man again to scare him off and hastily returns to the cabin.
As night falls, the five friends gather around a bonfire sharing ghost stories and eventually meet a local college student named Grim. He approaches them with his dog, Dr. Mambo, and, despite his quirky demeanor, they invite him to join after he offers them marijuana. Once it starts to rain, Grim leaves to take care of his camping gear, prompting the group to retreat into the cabin for shelter. Later that night, a knocking at the door reveals the diseased hermit seeking help after Bert shot him. The man’s condition is dire; when he attempts to take their car, he vomits blood, and Paul ultimately sets the man ablaze, causing him to flee back into the woods, where he collapses in the lake.
The following morning, a deputy named Winston arrives and assures Paul that he will call a tow truck. Jeff and Bert venture out down the lakeshore and ask a nearby woman for a ride into town, only to discover her connection to the hermit they killed, prompting them to leave in haste. During this time, Karen, unaware of the danger, drinks tainted lake water and soon falls ill, developing rotten boils on her thighs. She is quarantined in the tool shed as tension rises among the group, fearing they may be infected too.
The next day reveals Karen’s worsening condition, and Bert realizes he is also infected. In desperation, he drives off to seek medical help. While Paul and Marcy try to assist Karen, Jeff escapes into the wilderness with their remaining beer, causing Marcy to express her anger at his abandonment. Meanwhile, Bert's attempt to seek help leads him to the convenience store, where he shows signs of infection and is bitten again by the same boy. Instead of receiving assistance, he is pursued by the boy’s father and his friends, who are intent on killing him.
Back at the cabin, Paul finds Marcy grappling with despair. Despite their anxiety about the spreading infection, they give in to their fears and desires, resulting in wild sex, although Paul grows alarmed at the risk of Marcy possibly being infected. After their tryst, Marcy discovers unsettling marks on her back, indicating a grim fate. Paul, overwhelmed, decides to head out for help, leaving Marcy alone. She soon begins to suffer physical deterioration as the marks worsen.
Paul, now desperately searching for answers, finds a body floating in the lake, confirming the disease’s horror. He becomes infected after falling into the contaminated water. In a shocking turn, Marcy finds herself under attack by an infected Dr. Mambo, who has viciously harmed Karen. Paul, horrified, manages to kill the dog but finds the remnants of Marcy's gruesome fate. Grief-stricken, Paul faces Karen, who is in a near-death state from the rot, and he ends her suffering with a shovel before trying to escape.
As Bert struggles back to the cabin with the rednecks pursuing him, chaos unfolds when he is fatally shot. Paul takes matters into his own hands, seeking vengeance on the attackers before embarking on a desperate search for Jeff. He encounters only Grim's lifeless body instead. Paul then commandeers a car after a realization of his worsening condition and drives to a party where Winston is present. In a moment of chaos at the party, Paul attempts to explain the danger but is unable to articulate the threat of the infection effectively. His warning goes unheeded, and he is soon knocked out by Winston.
When Paul regains consciousness, he is in a hospital where doctors question him about the source of the infection. While dazed, he reveals the disease's marks on his belly, but the medical personnel determine they are ill-equipped for the situation and plan to transfer him to a larger facility. However, his driver turns out to be Winston, and in a tragic miscommunication, Paul tries to warn him about the contaminated water, only to manage to utter "water" in his weakened state.
As fresh chaos ensues, Jeff reemerges from hiding only to be shot by the redneck police, who dispose of his body alongside others in a gruesome pile. Meanwhile, Paul is abandoned in a stream by Winston, sealing the fate as his infection begins to seep into the water supply, ultimately threatening anyone who comes into contact with it. The cycle of horror continues as children unknowingly collect tainted water for their lemonade stand, which finds its way back to the local townspeople, further spreading the invisible menace that has erupted from that seemingly innocent cabin in the woods.
