In 1962, Frank "Tony Lip" Vallelonga, a tough bouncer from an Italian-American neighborhood in the Bronx, is searching for work while the nightclub he typically works at is closed for renovations. Known for his knack for resolving conflicts with his fists and his ability to charm his way out of tough situations, Tony is presented with an unconventional job opportunity. He's hired to be the driver and protector for Dr. Don Shirley, a highly-educated and sophisticated African-American classical pianist. Dr. Shirley is embarking on a concert tour that will take him through the racially charged southern United States, and he needs someone who can navigate the dangers of the era's deep-seated racism and segregation.

As they embark on the journey, Tony and Dr. Shirley are faced with the harsh realities of the Jim Crow South. Their relationship is initially strained due to their clashing personalities and disparate backgrounds. Tony, with his brash and unrefined manners, contrasts sharply with the dignified and erudite Dr. Shirley. However, as they encounter various forms of discrimination and bigotry, they are forced to rely on "The Negro Motorist Green Book," a guide that indicates the few establishments safe for African-Americans. Through their experiences on the road, the pair begin to challenge each other's perspectives, confronting their prejudices and forming an unexpected bond.