The novel begins in August of 1960. Jack Duluoz (alter-ago for author Jack Kerouac) is in San Francisco, hung-over. He missed his chance to go to Big Sur and stay at the cabin of his friend and fellow writer Lorenzo Monsanto (alter-ego for friend, Lawrence Ferlinghetti). Sitting in the hotel room alone, Jack realizes, "One fast move or I'm gone." So he gets himself to Big Sur, by bus followed by a long, tiring walk. He finds the heights of the cliffs above the sea to be both terrifying and awe-inspiring.
Time alone at the cabin is exactly what Jack needs. He resolves not to kill any animals and instead feeds the birds, squirrels, and mice. At night he sits by the sea and writes down the words he hears it speaking. The resulting poem is appended to the end of the text. While existing in relative peace, Jack identifies certain "signposts" that indicate something is wrong. Because he's writing in reflection, he makes it clear that there is a grand episode of delirium on the way, and that he'll get to it in his narration in time.
When Jack returns to San Francisco after three weeks, Monsanto informs him that he received a letter from Jack's mother bearing news of his cat's death. This hits Jack hard; it constitutes one of the "signposts" of death and madness. While in the city Jack meets up with many members of the gang – all alter egos for other members of the Beat Generation who spent time with Kerouac. The time in the city is largely devoted to drinking heavily and talking excessively. Among the other characters are Dave Wain, and his girlfriend Romana. Dave is a writer and fantastic driver, who takes the gang everywhere in his jeep named "Willie." He brings with him a teenage admirer named Ron Blake who represents the wannabe Beat kids, and who look up to men like Jack.
Soon enough Jack gets Dave to drive him to Cody Pomeray's place in Los Gatos. Cody is Jack's dear friend (alter-ego for Neal Cassady, also known as Dean Moriarty in On the Road). On the trip to Los Gatos, Jack and Dave lament the way America has changed over the last ten years. Jack himself laments the rift between the image people expect of him (the happy 25-year-old from On the Road) and the man he actually is (a run-down, cynical 40-year-old). In Los Gatos Jack is disappointed that he and Cody never have time to talk alone like they used to. He also sees Evelyn, Cody's wife, and explains that the three of them used to have a very functional three-way-relationship. Evelyn thinks she and Jack will be together in another life, and Jack is more than happy to believe so.
Next they head to a tuberculosis (TB) hospital to visit their sick friend, George Baso. Jack is again reminded of mortality and feels sick at the thought of the permanent condition of death. The whole gang ends up at Monsanto's cabin in Big Sur, though Jack concludes that he's desecrating the place by bringing others there. After the retreat in the woods is over, Cody brings Jack back to the city to meet his mistress, a slender blonde woman named Billie who lives with her four-year-old son Elliot. She and Jack fall for each other immediately; Cody leaves them alone, they sleep together, and Jack ends up staying with her for a week. He mostly just drinks and sits in the same rickety chair all day, despite frequent visits from his friends and attempts to make him eat instead of drinking all day.
Jack's mind begins to deteriorate, probably as the result of a week-long drinking binge. Billie has fallen completely in love with him and wants him to marry her, though Jack maintains that he's not capable of such commitment. He decides to bring Billie, Dave, and Romana out to the Big Sur cabin for a few weeks. It's only downhill from there; Jack's delirium tremens get increasingly worse at Big Sur, culminating in a devastating night of visions, paranoia, shakes, spiritual hallucinations, and sickness.
The delirium nightmare continues until after dawn, at which point Jack falls asleep and wakes up feeling perfectly fine again. In this relieved, rested, enlightened state, Jack concludes that everything will be OK on the long run. He looks forward to returning home to New York, to his mother and his buried cat. "There's no need to say another word," he finishes.