In the Bronx in 1962, Italian-American bouncer Tony Lip searches for new employment while the Copacabana is closed for renovations. He is invited to an interview with Dr. Don Shirley, an African-American 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 Negro Motorist Green Book, a guide for African-American travelers to find motels, restaurants, and filling stations that would serve them in the Jim Crow South.^[9]

Tony and Don initially clash as Tony feels uncomfortable being asked to act with more refinement, while haughty Don is displeased 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 that Don receives from his hosts and the general public when he is not onstage. In Louisville, Kentucky, a group of white men beat Don and threaten his life in a bar before 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 eloquent 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. Don is later found in a homosexual encounter with a white man at a pool, and Tony bribes officers to prevent his arrest. The two were arrested in Mississippi after a police officer pulls them over late at night in a sundown town, and Tony punches the officer after being insulted. While they are incarcerated, Don asks to call his lawyer and instead uses the phone call to reach Attorney General Robert F. Kennedy, who pressures the governor and police officers to release the two.

On the night of Don's final performance in Birmingham, Alabama, he 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 leave the venue and instead have dinner at a black blues club, where Don joins the band on piano. The pair head north in an attempt to make it home by Christmas Eve but are caught in a blizzard. They are then once again pulled over by a police officer. Worried they're about to get the same treatment, both are surprised when the officer turns out be friendly and only pulled them over because he noticed one of their tires was about to go out. The officer then helps them fix a flat tire and they're able to make it home. Tony invites Don to have dinner with his family, but Don declines. Sitting alone at home, Don changes his mind and returns to Tony's home, where he receives a surprisingly warm welcome by Tony's extended family.