Retired detective 'Big' Bob Carter and his wife Ethel are traveling from Cleveland to San Diego through the New Mexico desert for their silver wedding anniversary; with them are their three children, Lynn, Brenda, and Bobby, Lynn's husband Doug and their baby daughter Catherine, and their two German Shepherds, Beauty and Beast. They stop at a gas station, where the elderly attendant suggests a different route through the hills, claiming it will save them a few hours. Not long after, their tires are punctured by a hidden spike strip, causing their car, which is towing a trailer, to crash.
Bob and Doug set off in opposite directions to find help while the rest of the family stays by the trailer. Beauty escapes, and when Bobby chases her into the hills, he finds her butchered. Horrified, he flees back to the trailer but falls off the hill on the way, knocking himself unconscious. A timid yet kind-hearted girl named Ruby protects him from her brother, Goggle. Meanwhile, Bob arrives back at the gas station, where he finds newspaper clippings detailing various disappearances in the area after recent nuclear tests at a mining town by the US government that caused the mutants' deformities, as well as a bag of what he deduces to be the valuables of missing victims. He confronts the attendant, who then commits suicide. Bob attempts to flee in an abandoned car but is subdued by the mutant leader, Papa Jupiter.
After Bobby is found by Brenda, Doug returns after heading towards the interstate. All he discovers at the end of the road is a huge crater filled with numerous abandoned cars and other belongings. When being pursued by Papa Jupiter, Bobby confesses his story to Doug and Lynn, just as Pluto and Lizard infiltrate the trailer. They attack and rape Brenda, who has stayed in the trailer with Catherine, while using a distraction of immolating Bob to divert the others. When Lynn and Ethel return to the trailer, Lizard shoots both of them before abducting Catherine and escaping with Pluto. Doug and Bobby return; Lynn and Ethel die shortly afterwards.
The next morning, Doug, along with Beast, sets out to rescue Catherine. He comes across an abandoned nuclear testing village through the miner town's cave system but is knocked unconscious by Big Mama. After awakening in an ice box containing previous victims' dismembered remains, he escapes and encounters Big Brain, who reveals the mutants' origins to him. Pluto appears and attacks Doug, but he manages to gain the upper hand and kill Pluto with his own axe before killing another mutant, Cyst. After ordering Lizard to kill Catherine, Big Brain is mauled to death by Beast. Ruby manages to take the baby from Lizard and escapes through the hills.
Back at the trailer, Brenda and Bobby build an explosive trap, which they set off when Brenda is attacked by Jupiter. Meanwhile, Doug catches up with Ruby, but Lizard attacks them before Ruby can hand Catherine over. A struggle ensues, and Doug defeats him with Cyst's shotgun. Ruby then gives Doug his daughter back. Lizard, still alive, aims the shotgun at Doug, but Ruby tackles Lizard off a cliff, sending them both falling to their deaths.
Bobby and Brenda find Jupiter wounded from their trap; Brenda kills him with a pickaxe. The siblings are reunited with Doug, Catherine, and Beast. As the survivors embrace, an unknown mutant watches them from afar through binoculars.
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