The story is set almost entirely in the fictional town of Castle Rock, Maine. The action centers on Cujo, a St. Bernard that belongs to Joe Camber and his family. Although Camber is somewhat fond of Cujo, he never bothers to get the dog vaccinated against rabies.
The omniscient narrator recaps the story of Frank Dodd, the Castle Rock deputy sheriff whose murder spree was the central episode in the first half of The Dead Zone. There are some hints in the story that Cujo might be possessed by Dodd and that Dodd is haunting the Trenton house.[citation needed] Except for these vague hints, and a closet which opens itself despite being latched and blocked with a chair, there are no supernatural elements in the book.
While chasing a rabbit in the fields around the Cambers' house, Cujo gets his head temporarily stuck in the entrance to a small limestone cave and is scraped on the nose by a bat which is resident therein and infected with rabies. As Cujo begins to succumb to the disease, Joe's wife and son, Charity and Brett, leave on a trip to visit Charity's sister, Holly, in Connecticut. Soon afterward, Cujo attacks and kills the Cambers' neighbor, Gary Pervier, a World War II hero who has become a misanthropic alcoholic. Joe goes to the Pervier home to check on Gary because they were going to Boston, only to find him dead. Before Joe is able to summon help, Cujo kills him as well.
The Trentons—Vic, Donna, and four-year-old Tad—are having problems of their own. Vic has discovered that his wife has been cheating on him with an itinerant furniture restorer and poet. In the midst of this household tension, Vic's fledgling advertising agency is failing, and he is forced to leave on a business trip to Boston and New York. Donna, home alone with Tad, takes their failing Ford Pinto to the Cambers' for repairs. However, the car breaks down when they reach the farm. With no one at the Camber home except for Cujo, a three-day struggle begins to outlast the dog in a siege of the stalled car.
Hunger, thirst, and fantasies of escape methods conspire to tease Donna and Tad during the hottest summer in Castle Rock history. During one escape attempt, Donna is bitten in the stomach and leg. She eyes the back door of the Cambers' home, planning on making a dash for it, but is afraid it may be locked and Cujo may get her, leaving her son all alone. So she and her son stay trapped in the car for two more days before the Castle Rock sheriff shows up.
The Castle Rock sheriff, George Bannerman, arrives, but he approaches what appears to be an abandoned car without his service revolver at the ready. Cujo jumps on him and kills him easily.
Vic, worried that his wife has not answered the phone at home, returns to Castle Rock and, having learned that Bannerman is not responding to his radio, heads out to the Cambers' residence. Donna eventually kills Cujo with a baseball bat but is too late to save Tad from dying of heatstroke. The Trentons are able to move on after Tad dies but not without great difficulty.