Willard Stiles, Crispin Glover is a social misfit who cares for his ill and verbally abusive mother Henrietta in a musty old mansion, living under the constant humiliation of his ruthless boss, Frank Martin, R. Lee Ermey who took over the Stiles family company after Willard's father Alfred died by suicide in 1995 and swore that Willard would keep his job as long as Henrietta lived. After discovering and failing to exterminate a growing rat colony in the basement, Willard befriends a white rat he names Socrates and quickly becomes consumed by this unlikely companionship.
At work, Martin locks Willard in the elevator, though his sympathetic co-worker Cathryn, Laura Harring, eventually releases him. That evening, he watches Socrates begin tearing up a newspaper, prompting him to train the now-expansive horde of rats, including Ben, a monstrously large rat who envies Willard's favoritism toward Socrates. After training the rats sufficiently, Willard takes them to Martin's home and orders them to chew up the tires on Martin's new Mercedes-Benz. While Willard initially rejects bringing along Ben due to his size, the stubborn rat sneaks along anyway and chews a hole in the garage door to join the others in destroying all four tires. A dog follows Willard in his hurried exit, and he places the animal in a bag with the rats before deciding to remove it later. The next day at work, an on-time Willard gleefully watches Martin arrive late and tired. While Willard explains to the rats that they must move out, Henrietta overhears him, assuming he plans to get rid of her. Startled by noises from the basement, Willard finds her dead the next morning, the basement stairs enabling the rats to spill out from below, including a rebellious Ben. At the wake, Willard learns that Henrietta refinanced the family home to pay Alfred's debts, resulting in the bank foreclosing on the property.
In Henrietta's bedroom, Willard finds an envelope from the coroner's office containing Alfred's effects, including the still-bloody pocket knife he evidently used to kill himself. Distraught, Willard attempts suicide with the knife until Socrates stops him. Attempting to comfort Willard, Cathryn describes her own mother's death and gives him a pet cat, with Socrates safely stowed in his pocket. In a scene set to the title song from the 1972 movie Ben, the rats, who have by now taken over the entire house, pursue and fatally overpower the cat.
Desperately lonely, Willard starts bringing Socrates to work with him. Despite a contract written by Alfred stipulating that he remain employed by the family company, Willard finds a note at his desk from Martin declaring that he is fired. While Willard pleads to keep his job, Martin's secretary Barbara Leach discovers Socrates in the supply room, and her screams alert Martin, who fatally bludgeons Socrates to death while Willard watches helplessly. Fed up with the torment, Willard finally snaps and hatches a plan to avenge Socrates' death with Ben. Loading the numerous rats into a company van, he confronts Martin and orders them to swarm upon Martin and kill him.
At home, Willard kills the remaining colony before ratproofing the house. Exhausted after the night's events, he is awakened by the doorbell and finds two policemen in the hallway, terrified by the shadows. Cathryn arrives, informing Willard that Martin's body has been found and that rumors claim he was murdered or eaten by animals. Coming face-to-face with Ben, Willard tries to leave the house but discovers that the leftover rats have chewed out his car tires. Accosted by the two officers, Willard retreats into the house and frantically attempts to prevent the rats from entering. Trapping himself in the kitchen, Willard is confronted by Ben, whom he tries to kill with a rat trap.
Believing Willard is insane, the police leave to call Bellevue Hospital and the health department. When Cathryn tries to enter the house, they warn her against it, explaining that she could be eaten alive. Ben, though severely injured, viciously attacks Willard as he tries to escape. The police and Cathryn watch as Willard, outlined in the upstairs window, kills Ben with his father's pocket knife.
The final scene reveals Willard in a psychiatric hospital, seemingly semi-catatonic and refusing to talk. A white rat appears in his cell, crawling into Willard's sleeve as Socrates used to. Believing that his friend has been reincarnated, Willard joyfully drops his semi-catatonic act and begins telling the rat his plans for an escape.
