Sal Paradise, the narrator of the story, is miserable and fed up with his mundane life when he meets a young man named Dean Moriarty during the winter of 1947. Dean is wild, irresponsible, and newly married to a girl named Marylou. Before long, Marylou and Dean split up and Dean goes to stay with Sal in New Jersey. Sal and Dean both want to travel and decide that they will eventually take a trip west together.
In the spring, Sal sees Dean off to Denver and decides to follow him when he has the money. A few months later, Sal hitchhikes all the way to Denver.
In Denver, Sal moves in with an old friend named Roland Major and learns that Dean is cheating on Marylou with a girl named Camille. After staying there for a short time, Sal decides to leave Denver and go to San Francisco.
When he arrives there, Sal stays with his friend Remi Boncoeur and his girlfriend Lee Ann outside of San Francisco. Sal is unhappy staying with the bickering couple and decides to take the bus out of California. .
He meets a pretty girl named Terry on the bus. They are attracted to each other and stay together in Los Angeles. Terry and Sal spend the next few weeks together, trying to make enough money for them to travel to New York together. Eventually, they realize that their relationship won't work out. Feeling depressed, Sal travels back to his aunt's home in Paterson, New Jersey and realizes how much he misses Dean.
Dean and Sal had not seen each other for about a year. Sal had stayed home for the entire time, going to school and finishing his book. Over Christmas in 1948, Sal is visiting his brother in Virginia when Dean, Marylou, and their friend show up at the door. Dean persuades Sal to join them. Dean, anxious to keep moving, tells Sal that he has left his girlfriend Camille and their new baby in San Francisco. The group drives to New Jersey and then to New York. .
The group travels to Louisiana and stay with a friend, Bull Lee, and his wife Jane.