The novel depicts Duluoz's mental and physical deterioration. Duluoz is unable to cope with a suddenly demanding public, and is battling with advanced alcoholism. He seeks respite first in solitude in the Big Sur cabin, then in a relationship with Billie, the mistress of his longtime 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, cannot emotionally provide for the increasingly demanding Billie, and finds himself increasingly unable to integrate into suburban life. Duluoz's inner turmoil culminates in his nervous breakdown during his third journey to Big Sur.
An addendum to the book contains Kerouac's poem "Sea: Sounds of the Pacific Ocean at Big Sur".