In 1962 New York City, bouncer Tony Lip searches for new employment while the Copacabana is closed for renovations. He is invited to an interview with Dr. Don Shirley, a black pianist in need of a driver for his eight-week concert tour through the Midwest and Deep South. Don hires Tony on the strength of his references.

They embark with plans to return to New York City on Christmas Eve. Don's record label gives Tony a copy of the Green Book, a guide for African-American travelers to find motels, restaurants, and filling stations that would serve them.

They begin the tour in the Midwest before eventually heading farther south. Tony and Don initially clash as Tony feels uncomfortable being asked to act with more refinement, while Don is disgusted by Tony's habits.

As the tour progresses, Tony is impressed with Don's talent on the piano, and is increasingly appalled by the discriminatory treatment which Don receives from his hosts and the general public when he is not on stage. A group of white men beat Don and threaten his life in a bar and Tony rescues him. He instructs Don not to go out without him for the rest of the tour.

Throughout the journey, Don helps Tony write letters to his wife, which deeply move her. Tony encourages Don to get in touch with his own estranged brother, but Don is hesitant, observing that he has become isolated by his professional life and achievements.

In the south, Don is found in a gay encounter with a white man at a pool, and Tony bribes the officers to prevent the musician's arrest. Later, the two are arrested after a police officer pulls them over late at night in a sundown town;

Tony punches the officer after being insulted. While they are incarcerated, Don asks to call his lawyer and uses the opportunity to reach Attorney General Robert F. Kennedy, who pressures the governor to release them.

On the night of the final performance on tour in Birmingham, Alabama, Don is refused entry into the whites-only dining room of the country club where he has been hired to perform. Tony threatens the owner, and Don refuses to play since they refuse to serve him in the room with his audience.

Tony and Don have dinner at a predominantly black blues club where Don joins the band on the piano, after playing Chopin's Étude in A minor. Tony and Don head back north to try to make it home by Christmas Eve.

Tony invites Don to have dinner with his family, but he declines and returns to his own home. Sitting alone in his home, Don decides to go back to Tony's home, where he is warmly greeted.

The end title cards show real life photos of the characters and state that Don continued to tour, compose and record songs, while Tony went back to his work at Copacabana. It also states that Tony and Don remained friends until they died within months of each other, in 2013.