Donna Trenton (Dee Wallace) is a discontented housewife whose life spirals after her husband, Vic, discovers her affair. Brett Camber (Billy Jacoby), the son of mechanic Joe (Ed Lauter), has only his St. Bernard, Cujo, for company. While chasing a rabbit, Cujo gets rabies from a bat, altering his behavior. As Cujo deteriorates, Brett and Donna head to Connecticut to visit family, using lottery winnings. When Donna and her son, Tad (Danny Pintauro), arrive to fix their car at the Cambers' home, Cujo, now rabid, attacks their neighbor, Gary Parvier (Mills Watson). Gary briefly fights off Cujo but is soon killed while trying to arm himself. Joe Camber goes looking for Gary, finds blood, and discovers Gary's body inside. Attempting to call the police, he encounters the now-dangerous Cujo, who attacks and kills him as well. When Donna and Tad arrive at the Camber house, their car's alternator fails. They are attacked by Cujo, causing Tad to panic. Trapped in the Pinto, they face the dog outside as Vic is away on a business trip. Donna tries unsuccessfully to start the car while the large St. Bernard charges at them.
Vic comes home to find his house vandalized by Steve Kemp, the man Donna had an affair with. He informs the Sheriff, suspecting Kemp may be behind Donna and Tad's disappearance since he has been calling with no response. The Sheriff issues a lookout for Kemp's car, which is soon found. Although Kemp admits to vandalizing, he denies seeing Donna and Tad. The Sheriff believes him and goes to investigate at the Camber house after learning that Donna was taking the car for repairs. The scorching sun makes it almost unbearable, but Donna realizes they will die outside. She decides to take action before they succumb to heatstroke or dehydration, even though the dog is unpredictable and escape attempts are thwarted by Cujo's aggressive behavior. After a break-in, the local Sheriff arrives but is quickly ambushed by Cujo before he can draw his weapon. Cujo knocks the gun from the Sheriff's hand, and a struggle ensues inside the barn, resulting in the Sheriff being fatally thrown off a catwalk by the massive dog. Determined to save Tad, Donna tries to go outside, but Cujo lunges from under the car and bites her leg, forcing her back inside. Eventually, a severely injured Donna attempts to run to the house but is confronted by Cujo again, with the car as her only refuge.
She notices a baseball bat at the base of a tall tree and comes up with a plan. While Cujo is distracted by a ringing phone, Donna exits the car to grab a baseball bat. Cujo faces her from the porch, and she confronts him. After a fierce struggle between the mother and the dog, Donna seizes a brief distraction and strikes Cujo with the bat until it breaks, leaving just a jagged piece. The dog lunges at her but lands on the broken handle, impaling itself. Cujo becomes motionless, seemingly dead. Donna pushes the dog aside and uses the sheriff's gun to smash the back window and rescue Tad, as all the handles were broken. Once inside the house, she revives her son, who had fainted from heat and dehydration. Suddenly, Cujo crashes through the kitchen window, attempting to attack them. Before he can do so, Donna shoots Cujo at close range, killing him instantly. Vic arrives at the Camber home to find the Pinto and the sheriff's car but no sign of Donna or Tad. Growing anxious, he calls for Donna, who appears outside carrying Tad, as the credits roll.