The novel depicts Jack Duluoz's mental and physical deterioration in the late 1950s. Despite having found mainstream success with his work, Duluoz is unable to cope with a suddenly demanding public, and is battling advanced alcoholism. He seeks respite first in solitude in the cabin at Big Sur, on the California coast, and later in a relationship with Billie, the mistress of his long-time friend Cody Pomeray (Neal Cassady). Duluoz finds respite in the Big Sur wilderness, but is driven by loneliness to return to the city, and resumes drinking heavily.
Across Duluoz's subsequent trips to Big Sur and interleaved lifestyle in San Francisco, he drunkenly embarrasses Cody by introducing Billie to Cody's wife, and finds himself unable to emotionally provide for the increasingly demanding Billie (who proves to be mentally unstable herself) and to integrate into suburban life. On Duluoz’s third and final trip to Big Sur, he brings friends Dave Wain and Româno Schwartz (Lew Welch and Lenore Kandel), along with Billie's son Elliot. The peaceful trip soon goes afoul when Duluoz’s inner turmoil culminates in him having several panic attacks. The group leaves the following day.
An addendum to the book contains a free verse poem by Kerouac, "Sea: Sounds of the Pacific Ocean at Big Sur", written from the perspective of the Pacific Ocean.
