The film begins with three men testing for radioactivity in the New Mexico desert. Suddenly a bloody man jumps into one of the men view, begging for help. Pluto, a mutant disfigured by nuclear testing stabs one of the men and violently bangs him on the ground. The other two men are then quickly slaughtered and chained to the back of a car, which is driven away.
Ethel Carter (Kathleen Quinlan) and her husband, "Big" Bob Carter (Ted Levine), a retired police detective, are traveling from Cleveland, Ohio to San Diego, California on their silver wedding anniversary. Also present is their daughter Brenda (Emilie de Ravin), son Bobby (Dan Byrd), eldest daughter Lynn (Vinessa Shaw), her husband Doug Bukowski (Aaron Stanford), their baby daughter Catherine (Maisie Camilleri Preziosi), and the German Shepherds, Beauty and Beast. While Big Bob talks to the gas station manager, we see a mutant grab Bobby's red sweatshirt out of the car and run off. Bobby and Brenda head away from the building and Bobby goes into a nearby outhouse. He is urinating when he sees someone watching him through the window. It was the mutant who stole his red sweatshirt from the car. After believing one of the family has seen the contents of the holdall, the attendant tells Bob of a shortcut through the hills which is actually the secret trap.
After driving a few miles along the shortcut, the tires are punctured by a hidden spike belt and the truck's wheels burst, causing the truck to crash into a nearby ditch. Bob walks back to the gas station for a tow truck, and Doug walks the opposite way to get help. Meanwhile, the remaining members of the family are being watched by someone through a pair of binoculars. Beauty runs off into the hills and Bobby chases after her, eventually finding her gutted corpse. Frightened and distraught, Bobby runs off, but slips and falls, knocking himself unconscious. A young female mutant named Ruby, who had stolen his sweatshirt, (Laura Ortiz) comes across him and is intrigued by him, while her brother Goggle (Ezra Buzzington) chews over the dead dog.
Later, Bob finally makes it to the station and finds the hysterical gas station attendant, who commits suicide by shooting himself in the head. In fear, Bob tries to flee from the scene in a car. But he gets attacked by the mutant leader, Papa Jupiter (Billy Drago), and gets carried off into the mining caves nearby by Jupiter, along with Jupiter's eldest son, Lizard (Robert Joy), and Pluto.
When Bobby awakes, he returns to the trailer and does not tell his family of Beauty's demise. Lynn tells him that they tried the CB and heard heavy breathing. Beast breaks free of his chain and runs into the hills where he finds what's left of Beauty. Doug returns from the road he traveled, a dead end which ended in a bomb crater filled with cars, with a fishing pole, a baseball bat, and a teddy bear. Bobby is worried about his father who has not yet returned; Doug promises Bobby they will search for Bob if he does not return by midnight. As they try to sleep, Pluto sneaks into the trailer, finds Brenda, and attempts to rape her. Outside the trailer, Bobby wakes up Lynn and Doug, telling them about the people in the hills, and of Beauty's death. Inside Pluto holds Brenda down and prevents her from screaming. The others are about to discover Pluto when suddenly, an explosion in the distance draws their attention. Discovering that Bob has been tied to a tree and set on fire, Doug runs into the trailer to fetch a fire extinguisher as Lizard slips inside unnoticed. As everyone unknowingly leaves the helpless Brenda alone with the two violent men, Lizard notices Pluto's unsuccessful efforts to rape Brenda. Furious, he throws Pluto off and does it himself. Pluto then sees Catherine in her crib and observes her as Lizard continues to rape Brenda.
Doug manages to put out the fire, and unties Bob, already dead, while Lynn returns to the trailer to see why Brenda is screaming and is greeted by Lizard, holding baby Catherine and Big Bob's gun while Pluto is holding Brenda. After Lynn hits him with a frying pan, Lizard disarms her and threatens Catherine with the gun. He forces open Lynn's blouse and sucks the milk from her breasts. Ethel enters with a large flat rock, attempting to pulverize Lizard, but Pluto calls out to warn him. Lizard, spotting her, shoots her in the stomach. Lynn then uses a screwdriver and stabs Lizard, who then shoots her in the head. Pluto and Lizard flee the trailer, holding Brenda and Catherine hostage. When Lizard hears Doug and Bobby approaching, he tries to shoot Brenda, but the gun is out of bullets. He promises Brenda that he will be back for her before fleeing with Pluto, who still has the baby.
Doug and Bobby return to the trailer, discover the bodies, and realize that Catherine has been taken. Goggle, the mutant who killed Beauty, watches the trailer through binoculars, but he is attacked and killed by Beast. The next morning, Doug goes off in pursuit of their attackers; Beast leads Doug through a tunnel that contains the graves of miners. Once out of the tunnel, Doug finds an abandoned nuclear testing village and enters the house where Catherine is kept, but is knocked unconscious by Big Mama (Ivana Turchetto), who he thought was busy watching television. He then awakes in an icebox where the mutants keep the bodies of their victims. He panics and bangs on the plastic cover, eventually knocking it loose. He returns to his task of finding Catherine, only to encounter Big Brain (Desmond Askew), who tells him the story of the mutants, who were mutated by the fallout from the nuclear tests, and then getting attacked by Pluto who breaks through a door. After a fierce struggle, during which Doug loses the ring finger and pinkie on his left hand, he is able to trick him by pretending to cry. Pluto laughs and gets momentarily distracted, giving Doug time to slam a screwdriver through his foot and the floor, pinning him down. He then takes a small American flag and shoves it through the back of Pluto's throat, and finally finishes him by slamming the blade of his own axe into his head.
Doug then surprises the mutant Cyst (Gregory Nicotero) outside the house and uses Pluto's axe to kill him, chopping his knee open and knocking him over the hood of a car, where he is axed in the back and is finally killed when Doug swings the pick end into his eye. Doug takes his shotgun and heads off. Big Brain tells Lizard to kill Catherine, but is killed by Beast. Lizard takes a cleaver and prepares to kill Catherine, but finds that instead of Catherine, it is a pig. Ruby has taken Catherine and run into the hills. Lizard knows this and begins to chase her, enraged by her deceit. Doug sees Ruby on the hill and chases her as well.
At the trailer, Ethel's body is stolen and dragged into the hills, and Bobby finds Papa Jupiter eating Ethel's heart. Jupiter pursues Bobby to the trailer, where Brenda releases gas from the propane tanks as Bobby runs inside, attaching a strip of matches to the sliding door behind him. Bobby binds Papa Jupiter's hand to the window. After he and Brenda escape, Jupiter breaks free of the bungee cord, and opens the sliding door, which strikes the matches and ignites the gas inside the trailer, causing it to explode.
In the hills, Ruby is about to return Catherine to Doug when Lizard attacks. Doug beats and then shoots Lizard in the chest, neck, and finally the shoulder. Ruby gives Catherine back to Doug, who does not notice Lizard stand up, having survived. Ruby throws herself at Lizard, plunging them over a cliff, stopping Lizard from shooting Doug and Catherine and sacrificing herself in the process. Bobby and Brenda walk through the ruins of their trailer and find Papa Jupiter still alive, though impaled. Brenda kills Papa Jupiter with a pickax to the head. Brenda then spots Doug with Catherine and Beast, and the four are reunited. As they celebrate their apparent victory, a pair of anonymous binoculars watches from the hills.