The story is set almost entirely in the fictional town of Castle Rock, Maine and centers on Cujo, a St. Bernard, that belongs to Joe Camber and his family. Cujo is a friendly and mostly cheerful dog, affectionate with Joe's son, Brett and well-mannered around children. Although Joe is fond of Cujo, he never bothers to get the dog vaccinated against rabies. 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 bitten on the nose by a bat and infected with rabies.
Joe's wife Charity plans to run away from her overbearing and abusive husband, and she is worried about Joe's negative influence on their son, Brett. Charity wins $5,000 in the state lottery, using a check and the gift of an automotive chain fall to bribe Joe into allowing her to take Brett on a trip to visit Charity's sister, Holly, in Connecticut. Joe, however, has his own plans; he'll take a pleasure trip to Boston with his cantankerous & alcoholic friend and neighbor Gary Pervier while Charity and his son are gone.
Soon after Charity and Brett leave, Cujo, now well into the sickness, attacks and kills Pervier, killing him in his own house. Joe goes to the Pervier home to check on Gary before they leave for Boston, only to find him horribly mutilated. He finds a pile of dog excrement in the hallway and suddenly realizes Cujo has gone rabid. Before Joe is able to call authorities for help, Cujo attacks Joe in Gary's kitchen and kills him as well.
The Trentons—Donna, Vic, and five-year-old Tad—are having problems of their own. Vic has discovered that his wife had been involved in an affair with a local tennis instructor and furniture finisher, Steve Kemp . 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. The car breaks down in Camber's yard and as Donna attempts to find Mr. Camber, Cujo appears and is ready to pounce. She climbs back in the car and Cujo starts to attack.
Donna and Tad become trapped in their vehicle, with the immense and powerful dog repeatedly launching himself at the car door, eventually crimping it shut. During one escape attempt, Donna is bitten in the stomach and leg, but manages to survive and escape back into the car. She considers running for the Cambers' home but is afraid the door will be locked and she will be subsequently killed by Cujo, leaving her son all alone, and abandons the idea.
Kemp, extremely bitter over being dumped by Donna, shows up at the Trenton home. When he finds nobody there, he ransacks the place in a fury. After doing so, he closes up his furniture business and sets out for Oregon to begin a new life.
Vic returns to Castle Rock after several failed attempts to contact her. He also learns from the police that Kemp is suspected of ransacking his home and possibly kidnapping Donna and Tad. However, in an effort to explore all leads, the state police send local Castle Rock Sheriff George Bannerman out to the Cambers' house. When George gets there, Cujo attacks and kills him. In desperation, Donna realizes that Tad is dying and she must act. She leaves her car for the last time and faces Cujo down with Brett's baseball bat, breaking it over his head and fatally stabbing him through the eye with the broken end. Vic arrives immediately afterward only to discover Tad dead of dehydration. Donna, having been bitten by the dog, starts to lose her own mind and attacks Cujo's corpse until paramedics are able to inject her with a sedative. She is remanded to medical care for rabies treatments. Shortly after, a worker from the Maine State Department of Health arrives, cuts off Cujo's head and takes it away for study.
The book ends with both The Trentons and The Cambers trying to go on with their lives; Charity gives Brett a new, vaccinated puppy they name Willie. Vic and Donna are gradually drawn back to each other, rekindling their relationship. A postscript reminds the reader that Cujo was a good dog who always tried to do the right thing by his owners, but the ravage of rabies drove him to violence. His remains were cremated and disposed of.
Frank Dodd is dead and the Maine town of Castle Rock is able to rest peacefully again. Now he has passed into legend and become the town's boogeyman. He is a memory and a myth to everyone except to young Theodore "Tad" Trenton, whose closet seems to harbor Dodd's spirit. As Tad sleeps at night his door will open on its own and a pile of blankets seems to stare at him. His parents, Vic and Donna, are worried but pass it off as a childhood fear.
Outside of town, Joe Camber owns a small auto repair business out of his barn. His son Brett helps him out when he's not playing with their 'friendly' dog Cujo. Upstairs in their house Joe's wife Charity stares at a lottery ticket that has just won her thousands of dollars.
Vic works for a small advertising company called Ad Worx. Ad Worx's main client is Sharp, a company that produces cereal. Ad Worx's big claim to fame is the Sharp Cereal Professor, who's become quite the cultural icon. Recently Sharp experienced major problems with one of it's products, Red Zingers. A single batch of cereal was contaminated with a dye that caused several children to become sick. The red dye made it appear as though they were throwing up blood and not the cereal. A major scare hit the country until Sharp explained the problem. Afterwards every late night comedian began making fun of the Sharp Cereal Professor and it became a major embarrassment for the Sharp Company. Vic and his partner, Roger Breakstone, are worried that if they don't come up with something great Sharp will drop them and they'll be out of a job. Vic and Roger plan to head out of town on a business trip in order to save the Sharp account.
It is the hottest summer on record. Everyone from the weather men to the old women are saying that it's just going to get hotter. One day Cujo is lying around the Camber farm trying to remain cool. He sees a rabbit and decides to give chase. The rabbit runs into a small hole and falls into a much larger cave. Cujo is too large to fit through the hole. His barking disrupts several bats who are sleeping, at least one of which is rabid. Cujo's barking aggravates the bats and they begin to bite and scratch him. Cujo flees after being hurt but the damage is already done. Cujo now has rabies and has never been vaccinated.
While Vic is at work and Tad is at day care, Donna is putting away groceries when Steve Kemp arrives. Kemp is a furniture repairman, tennis player, poor sport, and Donna's lover. This time, however, Donna is breaking up with him. Kemp does not take the news very easily and does not like being the one dumped. He physically threatens Donna but decides to leave. Back at his office Kemp decides to leave town, but not before mailing a letter to Vic exposing Donna's daytime adventures.
Charity wants to take Brett to see her sister in New Hampshire, but knows Joe won't let her. Charity convinces Brett to go but that doesn't mean Joe will let him leave. She uses some of the lottery money to buy Joe a new chainfall and promises to let him take Brett on one of his hunting trips if she can take Brett to her sister's. Joe agrees but secretly decides to go on a trip with his buddy Gary Pervier using some of the money himself.
Vic gets Kemp's letter. He doesn't quite know what to do but decides to talk to Donna. Donna explains that it was only temporary and that she just recently broke it off. Vic considers staying home but decides that he needs to be there and that the break may be just what he needs to think it out.
Early the next morning Brett wakes up too anxious to sleep. He goes outside to feed Cujo but it is a foggy morning. Wandering around Brett suddenly hears Cujo growling and sees him walk out of the fog, fully rabid. Brett's talking gets through to Cujo and he leaves Brett alone. Brett worries and tells his mother. Charity is afraid that Joe will use this to keep Brett there and decides to tell him when they arrive. Joe drops Charity and Brett off at the bus station. This is the last time Brett and Charity see Joe alive. The two leave for Charity's sister's place. That same morning Vic and Roger leave on a plane to Boston.
Donna and Tad go out for groceries and lunch. On their way back Donna's Ford Pinto begins jerking and breaks down just down the street from their house. It had done this before and Vic thought it was the needle valve. Vic suggested Camber's place but last time they went out there Donna did not like Joe or his large, but friendly, dog. Vic calls and suggest Cambers, which is closer, or a Ford Dealership, which wouldn't have a giant dog. Donna decides on the Ford Dealership.
The next morning WWII Veteran and Camber's neighbor Gary Pervier wakes up and finds Cujo outside his home. Gary recognizes rabies and tries to get inside his home to his shotgun. Cujo breaks through the screen door and kills Gary. Meanwhile, Joe's cleaning up a pile of feces that Cujo left in the garage. Joe thinks that it's just Cujo's way of showing his dissatisfaction over all his owners deciding to leave. Joe goes down to get Gary when he notices blood and a broken screen door. He finds Gary's corpse and another pile of feces. Joe figures out that Cujo has gone rabid, closes the front door, and tries to call the police. But Cujo is actually in the house, the basement to be more specific, and attacks Joe when his back is turned.
Donna tries to hire a babysitter for Tad but he strongly refuses. He's afraid that the monster in his closet will get him if she's not there. Donna lets Tad come along and brings some snacks and milk. However, Donna does not believe the Pinto will make it to the Ford Dealership and decides to head to the Camber's.
The Pinto barely makes it to the Camber's. Donna looks around and finds Cujo and recognizes that he's rabid. Donna and Tad run into the car and quickly roll up the windows. Donna tries to restart the car but it needs to cool down before it can work again. Meanwhile, they are trapped in the car while Cujo is outside.
Vic thinks of an idea to save themselves and Ad Worx. Their plan is to not come up with an entirely new idea but have one more commercial with the Sharp Cereal Professor where he will make an apology and explain the situation. Then they could go onto another idea. Roger buys it and goes along. The actor who plays the Professor also goes along. But they are unsure if the Sharp Company will go along.
Later that night Donna tries the car again but it still will not work. The battery is too getting too low. Donna remembers a package by the mailbox and realizes that the next day the mailman will come by and she can use the horn to get his attention. Unbeknown to her, Joe canceled the mail for the time he intended to be gone. Donna thinks she can make it to the Camber's front door if she ran. However, the door could be locked and she wouldn't be able to beat Cujo if she had to run there and back. She is afraid that Tad would witness his mother being eaten alive. She instead stays in the car and waits for a better time.
Kemp is still angry over being dumped by Donna. He returns to Castle Rock to the Trenton's house. He lets himself in and begins destroying everything on the bottom floor. He breaks glass and photos, overturns furniture, throws all the kitchenware around, and even ejaculates on the Trenton's bed. Kemp finds a note from Donna saying they have gone to the Camber's (presumably someone else comes around and has a key) but erases it and writes a note of his own. Kemp leaves with the house a mess.
Charity is enjoying her relatives but Brett is worried about his dog. Brett also begins to criticize his relatives. Like how his aunt shows off her credit cards or how her husband shows off a fancy jukebox. Brett says that he shouldn't be bragging if he didn't make it himself. Charity tries to explain that while Joe works hard with his hands in the garage, her brother-in-law works hard in an office. But Brett doesn't seem to get it.
Donna tries to make a run for the front door. She leaves the car but cannot see Cujo. She realizes that he is just in front of the car. Cujo attacks and bites her leg and stomach. After a large struggle Donna gets inside the Pinto and closes Cujo out. Cujo begins ramming the door denting it, even breaking the glass. Donna and Tad are safe in the car but Donna no longer believes she can run to the door with Cujo right outside the car or with her leg so badly injured. Also, she has been given rabies by Cujo.
Vic becomes worried when he cannot reach Donna at the house. He calls the sheriff's office and they check out his place. Vic receives a reply and hears about the vandalism. Vic informs them about what happened between Donna and Kemp and says that it was probably him. Vic returns home leaving Roger to work things out with the Sharp Company.
Vic comes home to Sheriff Bannerman and Attorney General Official Masen. Vic describes the affair and Kemp. Masen calls for Kemp's arrest but has his doubts. What he's wondering is if Kemp trashed the house and kidnapped Donna and Tad why is the Pinto gone? And why would Kemp leave a note specifically for Donna if he didn't take them? The whole situation doesn't seem to make sense. Vic then says that she wanted to take the Pinto into the Camber's for repairs. Masen doesn't think that lead will go anywhere but sends Bannerman to check it out.
Bannerman arrives and finds the Pinto. He checks it out before calling it in. Cujo surprises him and bites his stomach. Before Cujo can get Bannerman's jugular Donna leaves the car and distracts him. Bannerman tries to get back to the car but his intestines are hanging outside of his body. He wills himself to get there but before he can open the door Cujo attacks and kills Bannerman.
Brett is worried about Cujo and his father again. Charity calls a neighbor and asks for him to check on Cujo. But the neighbor gets distracted by his own problems and doesn't go. Charity decides to go home early. Charity wanted Brett to experience life outside of Joe and Castle Rock. But this trip made her realize that Brett is too much of Joe's son and doesn't fit into her sister's higher lifestyle. She decides to return and won't divorce Joe. She's still going to try to get a better life for Brett but doing it in Castle Rock.
Vic is still worried. Kemp had been arrested but swears he did not take Donna and Tad. Masen informs him that Bannerman has not been heard from. Vic goes upstairs and sits in Tad's room. Suddenly the closet door opens and he can hear Tad's voice. He freaks out and leaves the house. Vic decides to check out the Camber's to ease his mind. On his way Vic finds Joe's car at Gary's and sees the two bodies. Vic races over to the Camber's.
Donna is getting anxious. Tad is severely dehydrated and convulsing. Donna notices a wooden bat in the grass and makes a run for it. Cujo chases and a battle ensues. The bat breaks and Donna uses the broken end to stab Cujo in the brain. Donna beats Cujo's corpse with the bat until Vic arrives. Vic enters the car but finds Tad dead. Donna pushes Vic away and gives Tad mouth to mouth. Vic enters the Camber's home (the door had been unlocked) and calls the police and paramedics. Donna gives mouth to mouth until the paramedics pull her away. She bites one and they eventually restrain her. A Vet comes and cuts off Cujo's head.
Charity receives a call. She is informed that Joe and Cujo have been killed. Her sister notes that while Charity is sad there seems to be a part of her that is excited for the future.
Vic learns that the Sharp Company signed Ad Worx for another two years, but not a day more. Donna is cured of rabies and the paramedic she bit got a rabies shot. The story circulated the newspaper and tabloids causing a large rabies scare in Maine. Charity uses the money to keep the farm and gets herself a job. Brett gets a new dog named Willie. In the end Donna and Vic save their marriage and attempt to get over the loss of Tad.