Off the Road recounts the history of Carolyn Cassady, wife of Jack Kerouac's traveling companion and On the Road's hero Neal Cassady. As Neal's wife and Kerouac's intermittent lover, Carolyn Cassady was well situated to record the inception of the Beat Generation and its influence on American culture.

Off the Road begins in the initial stages of Kerouac and Neal Cassady's friendship, when Kerouac was a struggling author trying to publish his first novel (1950's The Town and the City), and documents important moments in the beat movement such as the success of On the Road and Allen Ginsberg's "Howl."