A captive woman, forced to bear mutant offspring, cannot deliver healthy children after giving birth to a stillborn and is killed by Papa Hades, the ruthless leader of the inbred mutant clan living in a nuclear testing village known as Sector 16 in the New Mexico desert. In the wake of the previous film, the United States Department of Defense moves in to occupy the site and eradicate what remains of the mutants. As a surveillance system is installed, Colonel Lincoln Redding and a small team of scientists come under attack from the hostile mutants.
A group of National Guardsmen in training, led by Sergeant Jeffrey “Sarge” Millstone, is dispatched into the desert to support the scientists. They arrive to find the base camp deserted after the mutants’ assault. When a faint distress call is detected, Sarge organizes a tense search and rescue through the rugged hills. Napoleon and Amber, who stay behind at the camp, manage to pull one missing scientist out of a camp portable toilet, but he dies before he can warn them. The two are soon ambushed by the mutants, who wreck their transport and seize their weapons, forcing them to flee into the hills to alert the others.
The rescue party is viciously attacked again; Mickey is dragged into a bolt-hole and killed by Stabber, and Sarge is accidentally fatally shot by Spitter’s friendly fire just as Napoleon and Amber reunite with the group. Spitter dies after one of the mutants sabotages his rappelling gear, leaving the survivors with dwindling supplies and few options to escape.
They locate Colonel Redding, who is mortally wounded and mentally unraveling from the assault. He warns the group about the mutants’ plan to capture women for breeding and reveals an exit route through the mining caves before taking his own life. After the group defeats Stabber, Missy is captured and taken into the mining caves by Chameleon, which spurs a dangerous rescue mission. Missy is eventually subjected to rape by the mutant leader, Papa Hades.
Stump abandons the others to escape on his own but is pursued and killed by Letch as he tries to descend the hill. Separating from Crank and Delmar, Napoleon and Amber cross paths with Chameleon, whom they manage to kill. While escaping Sniffer, they are aided by a nonviolent mutant named Hansel; Sniffer confronts Crank and Delmar, shoots Delmar with one of their M4 carbines, and is killed by Crank in retaliation. Hansel guides them toward the exit, but Delmar dies from his wounds at the mine doorway. Napoleon joins Amber in a mission to rescue Missy. Crank, who is attempting to unlock a blast door, dies when a crate of dynamite explosions claims him.
After destroying Letch, Napoleon and Amber locate Missy, who is being savagely raped by Papa Hades. They distract the mutant leader and free her, but Hades returns for a brutal confrontation, and the trio manages to subdue and kill the tyrannical mutant with a bayonet. As the survivors prepare to leave the mines, they are watched by an unknown mutant using their surveillance equipment, suggesting that danger may still lurk in the desert.
