Sal Paradise, an author and university student, resides in Paterson, New Jersey with his aunt. He often hangs out with his quirky, creative friends in New York City. Through his friend Chad King, Sal meets Dean Moriarty, a young individual fresh out of a correctional facility in New Mexico. After spending the winter in New York, Dean relocates to Denver when spring arrives. A couple of months later, Sal travels to Colorado to join him.

Sal travels westward by hitchhiking, discovering more about himself and the fascinating individuals he encounters throughout his journey. Upon reaching Denver, he reunites with a circle of friends from New York. Sal shares an apartment with his buddy, Roland Major, but is eager to catch up with Dean, who is constantly juggling his time between his spouse, Marylou, and his lover, Camille. Sal spends time exploring Denver with Dean and their mutual friends, attending a party in Central City. After several weeks, he departs for San Francisco by bus.

In San Francisco, Sal relocates to live with his buddy, Remi Boncoeur, and Remi's partner, Lee Ann. Remi secures a position for Sal as a special police officer at a facility for foreign employees. Sal despises collaborating with the fellow officers, who are unhappy and close-minded. A few months later, Sal departs from San Francisco and heads to Los Angeles. During the bus ride, he encounters Terry, a young Mexican-American female, and they develop romantic feelings for each other.

Sal accompanies Terry to her native Sabinal, a town close to Bakersfield. There, he encounters her relatives, settles into a tent with Terry and her little boy, Johnny, and starts working as a cotton picker. However, he quickly discovers that his earnings are insufficient to provide for Terry and her child. Sal convinces Terry to relocate with her family, and he goes back to his New York life by himself.

During the Christmas season a year later, Sal and his aunt travel to Virginia to see family members when Dean, Marylou, and Ed Dunkel show up from California. Sal leaves with them, initially heading to New York and then to Louisiana, where they meet their friend Old Bull Lee in New Orleans. Sal, Dean, and Marylou return to San Francisco, where Sal and Dean have more wild adventures. Dean starts living with Camille, but Sal eventually grows tired of Dean's chaotic behavior and decides to take a solo bus trip back to New York.

As another year goes by, Sal journeys westward once more, first to Denver and then to California. Upon visiting Dean and Camille in San Francisco, both men are kicked out by Camille. Sal and Dean then opt to head back to New York together. En route, they indulge in a crazy week of car theft and drinking in Denver, followed by a reckless drive to Chicago where they spend several days enjoying jazz and bop music. Upon reaching New York, Dean quickly falls for a woman named Inez.

During springtime, Sal departs from New York and travels westward once more. He pauses in Denver, reconnects with a few past acquaintances, and intends to visit Mexico. After a fortnight, Dean is drawn to the allure of the open road and joins Sal. Accompanied by a fresh companion, Stan Shephard, Sal, Dean, and Stan embark on their Mexican adventure in one of Dean's dilapidated vehicles.

Traveling southward through Colorado, New Mexico, and Texas, they eventually enter Mexico, thrilled to experience a new country. They are captivated by the welcoming locals and the stunning desert scenery. In Gregoria, they encounter a young man named Victor who provides them with marijuana and escorts them to a brothel. There, they indulge in an afternoon of drinking, dancing, and engaging in sexual activities with multiple women. Later that night, they depart Gregoria and rest on a roadside within the humid jungle, only to awaken enveloped in perspiration and insects.

Feeling as though they've merged with the jungle, they continue their journey toward Mexico City. Along a forested path, they encounter a group of young indigenous girls whose innocence and unpretentious lifestyle leave a profound impact on Sal and Dean.

Mexico City presents a sudden, disorderly juxtaposition to the serene, natural jungle. Sal, Dean, and Stan wander through the bustling streets, taking in all the sights and sounds of the packed, cacophonous metropolis. Sal contracts dysentery, falling severely ill, yet Dean abandons him in Mexico to reunite with Inez in New York. After recovering, Sal journeys back north, reaches New York, and falls for a woman named Laura.

Sal encounters Dean once again when Dean pays him a visit in Manhattan. The meeting is short and filled with discomfort; Sal has become more engaged with his New York companions, while Dean struggles to articulate his feelings towards Sal. As Sal leaves to attend a concert with his friends, Dean departs New York on a cold night, journeying back to California by himself. Subsequently, Sal spends time on a pier, reminiscing about their bond and shared experiences.