Cujo, a friendly and easygoing St. Bernard, chases a wild rabbit and inserts his head into a cave, where a rabid bat bites him in the nose. Meanwhile, the Trenton family — advertising executive Vic (Daniel Hugh Kelly), housewife Donna (Dee Wallace) and their sensitive young son Tad (Danny Pintauro) — take their car to the rural home of abusive mechanic Joe Camber (Ed Lauter) for some repairs, where they meet Cujo, who is the Camber family's pet, and get along well with him.
Donna notices Cujo's bitten nose, but thinks little of it. Later, Vic and Donna's marriage is tested when Vic learns that Donna is having an affair with her ex-boyfriend from high school, Steve Kemp (Christopher Stone), while Vic's advertising for a cereal commercial is failing. Charity (Kaiulani Lee) and Brett (Billy Jacoby), Joe's wife and son leave the house for a week to visit Charity's sister Holly. When the bite infection begins to set in, Cujo is able to refrain from threatening Brett, but soon succumbs and is driven mad. He kills their alcoholic neighbor, Gary Pervier (Mills Watson), and his owner Joe (who is attacked before he can call the authorities).
Vic goes out of town on a business trip, as Donna and Tad return to the Camber's house for more car repairs. Cujo attacks them, and they are forced to take shelter in their Ford Pinto. Donna tries to drive home, but the car's alternator dies and the two are trapped inside. The hot sun makes conditions nearly unbearable, and Donna realizes that she must do something before they both die from heatstroke or dehydration. However, attempts at escape are foiled by Cujo repeatedly attacking the car and breaking a window in the process. Vic returns home to rekindle his marriage, only to find Donna and Tad missing and his house vandalized by Kemp. He suspects the possessive Kemp of kidnapping, but the police realize his wife and son might be at the Camber's house.
The local sheriff, George Bannerman (Sandy Ward), arrives at the mechanics house and has a brief standoff; before he can draw his gun, Cujo kills him, knocking him off the catwalk in the barn and mauling him to death. Later, Donna takes advantage of a momentary distraction and hits Cujo with a baseball bat until it breaks, leaving only a jagged handle. Cujo jumps at her and is impaled in the stomach by the broken bat. Donna takes the sheriff's gun and retrieves Tad, who is dehydrated and overheated. After Donna revives Tad inside the kitchen, Cujo, now recovered, breaks through the kitchen window and tries to attack Donna. However, Donna shoots Cujo dead, before Vic arrives and reunites with his family.
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