In a tranquil, small American town, a heart-warming St. Bernard named Cujo chases a rabbit which leads him to a hidden cave. Unfortunately, Cujo sticks his head into a bat-infested hole and suffers a bite from a rabid bat. Over a short period, the once gentle family pet begins to undergo a frightening transformation as the disease takes hold, altering its demeanor to one of unpredictable aggression.

Meanwhile, the Trenton family faces its own set of challenges: the marriage between Donna and Vic is strained due to Vic's demanding advertising job and Donna's infidelity. Their son, Tad, has his own fears, suffering from terrifying nightmares of a monster in his closet. Vic's work demands escalate when a crisis arises with a cereal campaign, leaving Donna and Tad to tend to the failing family car. Seeking a mechanic's assistance, they visit the rural home of the mechanic, which ironically is also where Cujo now roams with his growing aggression. Ignorant of the danger, Donna and Tad find themselves stranded in their faulty car, confronted by the now-menacing beast, setting off a relentless struggle for survival.