Rancher Cole Hillman seeks the help of college president Elgin Clark to combat thousands of rabbits that have invaded the area after their natural predators, coyotes, were killed off. Elgin asks for the assistance of researchers Roy and Gerry Bennett because they respect Cole's wish to avoid using cyanide to poison the rabbits. Roy proposes using hormones to disrupt the rabbits' breeding cycle and takes some rabbits for experimentation. One is injected with a new serum believed to cause birth defects. However, the Bennetts' daughter Amanda loves the injected rabbit, so she switches it with one from the control group. Amanda is then given the injected rabbit as a pet, but it soon escapes.
While inspecting the rabbits' old burrowing areas, Cole and the Bennetts find a large, unusual animal track. Meanwhile, Cole's son Jackie and Amanda go to a gold mine to visit Jackie's friend Billy, but find him missing. Jackie finds more of the animal tracks in Billy's shed, while Amanda goes into the mine and runs into an enormous rabbit with blood on its face. Screaming in terror, she runs from the mine.
Mutilated bodies begin to crop up around town, including those of Billy, a truck driver, and a family of four. Elgin, the Bennetts, Cole, and Cole's two ranch hands Frank and Jud go to the mine to try to kill the rabbits with explosives. As Elgin and Cole set charges on top of the mine, Roy and Frank enter the shaft to get pictorial evidence. Outside, a rabbit surfaces and attacks Jud before Gerry can shoot it. Roy and Frank escape the rabbits in the mine and run outside as the explosives are detonated.
The explosives fail to kill the rabbits, and that night they attack Cole's ranch, killing Jud while Cole, Frank, Jackie, and Cole's housekeeper Dorothy escape into the storm shelter. The rabbits make their way to the general store, killing shopkeeper Mildred (Francesca Jarvis) and eating everyone else they find in the small town of Galanos before taking refuge in the buildings for the day. In the morning, Gerry and Amanda leave to avoid the coming press, but get stuck along a sandy stretch of road. Roy and Elgin update Sheriff Cody on the situation and, after realizing the rabbits have escaped the mine, call in the National Guard. As night falls, the rabbits leave Galanos to continue their rampage, making their way to the main town of Ajo and eating and killing everyone in their path. Cole proposes using a half-mile wide stretch of electrified railroad track as a fence to contain and kill the rabbits. They recruit a large group of people at a drive-in theater to help herd the rabbits with their car lights, with assistance from the machine gun fire of the National Guard.
Thousands of rabbits make their way into the trap, where they are shot and electrocuted. At the film's ending, Cole tells Roy that normal rabbits, as well as coyotes, have returned to the ranch.
The ending shows Roy and Gerry running on a grassy field where a normal rabbit is shown sitting on the grass before the end credits roll.
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