A captive woman, forced to breed mutant children, is unable to provide healthy offspring after giving birth to a stillborn and is killed by Papa Hades, leader of the inbred mutant clan living at a nuclear testing village in the New Mexico desert, designated as Sector 16. Following the events of the first film, the United States Department of Defense sent a military army to occupy the location and exterminate the remainder of the mutant clan. Colonel Lincoln Redding and a trio of scientists who are working in that area on installing a surveillance system are attacked by the mutants.
Later, a group of National Guardsmen in training led by Sergeant Jeffrey "Sarge" Millstone are sent into the desert to resupply the scientists. They arrive to find the base camp abandoned after the mutants' attack. When the soldiers pick up a faint distress call, Sarge organizes a search and rescue mission through the hills. Napoleon and Amber, who stay behind at the camp, find and retrieve one of the missing scientists out of the camp's portable toilet, but he dies before he can warn them. The two are then attacked by the mutants, who destroy their transport and steal their weapons, forcing them to run into the hills to warn the others. The search party is attacked by the mutants; Mickey is pulled into a bolt-hole and killed by Stabber, and Sarge is accidentally shot dead by Spitter's friendly fire just before Napoleon and Amber reunite with the group. Spitter is killed after one of the mutants sabotages his rappelling gear as the others try to lower him down the hill. With their remaining gear stolen, they are forced to try to find another way to escape.
The remaining troops soon locate Redding, mortally wounded and unhinged from the mutant's attack. He warns them of the mutants' plans to capture women for breeding and reveals an exit route through the mining caves before committing suicide. After the group kills Stabber, Missy is captured and taken into the mining caves by Chameleon, forcing the other troops to rescue her. Stump leaves the group to escape on his own before being pursued and killed by Letch while attempting to climb down the hill. Separating from Crank and Delmar, Napoleon and Amber cross paths with Chameleon, whom they manage to kill. While escaping Sniffer, they are rescued by a nonviolent mutant named Hansel; Sniffer encounters Crank and Delmar, shoots the latter with one of the group's M4's and is killed by Crank in retaliation. While Hansel leads them to the exit, Delmar dies from his wounds after arriving the mines' doorway. Napoleon joins Amber to save Missy. Crank, who is attempting to unlock the blast door, dies when accidentally triggering an explosion of a crate of dynamites that he attempts to take with him.
After killing Letch, Napoleon and Amber locate Missy who was being savagely raped by Papa Hades. After distracting him, they manage to free her, but Hades soon returns and attacks them, triggering a vicious fight until the trio finally subdues and kills the mutant leader with a bayonet. As the survivors prepare to depart the mines, they are watched by an unknown mutant using their surveillance equipment.
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