Kilgore Trout is a widely published, but unknown writer who is invited to deliver a keynote address at a local arts festival in distant Midland City. Dwayne Hoover is a wealthy businessman who owns much of Midland City. Unfortunately Dwayne is mentally unstable and is undergoing a gradual mental collapse. Kilgore arrives in Midland City and, by happenstance, piques the interest of Dwayne. A confused Dwayne demands a message from Kilgore, who hands over a copy of his novel. Dwayne reads the novel, which purports to be a message from the Creator of the Universe explaining that the reader - in this case Dwayne - is the only individual in the universe with free will. Everyone else is a robot. Dwayne believes the novel to be factual and immediately goes on a violent rampage, severely beating his son, his lover, and nine other people before being taken into custody.

Kilgore has published dozens of novels and scores of short stories, but remains entirely unknown. His fiction has generally been used as filler material to pad the length of pornographic books and magazines. Strangely, Kilgore receives an unlikely invitation to speak at the Midland City arts festival. Kilgore decides to speak at the festival to represent unknown, failed and desperate writers. He intends to deliver a stinging rebuke full of bitter commentary to what he imagines will be a crowd of effete patrons of the arts. Using the funds advanced to him by the festival organizer, Kilgore sets out on a long trek to the Mid-West. Kilgore hitchhikes across the country to save money. He tries to sleep in an adult film theater to avoid renting a hotel room, but he is evicted in the early morning hours when the theater closes. Kilgore is then robbed and beat up and ends up spending the night in police custody. Nearly completely destitute, he continues his westward voyage.

Meanwhile Dwayne Hoover, an affluent citizen of Midland City, suffers the final stages of a mental breakdown. Dwayne's adult son has disappointed him and his wife's suicide has left him a widower. He runs an automobile dealership, owns an interest in most Midland City businesses and carries on a discreet monogamous affair with his secretary. But he also continues to go gradually insane due to a chemical imbalance, even as other Midland City residents approach him for various forms of financial assistance. Dwayne moves through Midland City and observes or recalls many trivial details about his earlier life.

After a long trip full of trivial details, Kilgore eventually reaches Midland City and enters a hotel lounge where he reviews some arts festival registration materials. By strange coincidence, nearly every other character presented in the novel is simultaneously either inside the same hotel lounge or at least nearby. Dwayne sits in the same lounge, mesmerized by Kilgore's shirt, which glows under the lounge's fluorescent lights. Dwayne suddenly lurches to his feet and demands a message from Kilgore. Kilgore furnishes a copy of one of his novels and Dwayne eagerly and quickly reads the book. Dwayne interprets the book to mean that he, Dwayne, is the only thinking, free-willed being in the universe. Everyone else is simply a robot programmed for Dwayne's amusement. He immediately sets out on a violent rampage, severely beating his son, his lover, and nine other characters.