Donald Walbridge Shirley was born in Pensacola, Florida, on January 29, 1927, the son of Jamaican immigrants: Stella Gertrude Shirley, a teacher, and Edwin S. Shirley, an Episcopal priest. His record label later advertised him as Jamaican-born, which is why Kingston is sometimes given as his birthplace in older sources; it is wrong. He started piano at the age of two and was playing the organ by three. After brief stays at Virginia State University and Prairie View College he studied with Conrad Bernier and Thaddeus Jones at the Catholic University of America in Washington, D.C., and took a bachelor's degree in music there in 1953. Two honorary doctorates later made him "Dr. Shirley." Some early biographies say he studied at the Leningrad Conservatory; his cellist Jüri Täht and his nephew Edwin both deny it, and Edwin said the label invented European training to make a Black musician from a Black school acceptable to audiences who would otherwise have ignored him.

His concert career began young. In 1945, at 18, he played Tchaikovsky's B-flat minor piano concerto with the Boston Symphony Orchestra, and a year later the London Philharmonic Orchestra performed one of his compositions. He was a finalist for the Rhodes Scholarship in 1949 and was invited that year to play at the Port-au-Prince bicentennial exposition in Haiti, where the president and the archbishop asked for a second performance the following week. Discouraged by how few doors were open to Black classical pianists, he put the piano aside for a time, studied psychology at the University of Chicago and worked as a psychologist, with a grant to study the relationship between music and juvenile crime. In a small club he quietly tested how audiences responded to variations in sound, using students planted in the room to record their reactions.

Music pulled him back. At Arthur Fiedler's invitation he appeared with the Boston Pops in Chicago in June 1954, and in 1955 he performed with the NBC Symphony at the Carnegie Hall premiere of Duke Ellington's Piano Concerto. He also appeared on television on Arthur Godfrey and His Friends. His first album as a leader, Tonal Expressions, came out on Cadence Records in 1955 and reached No. 14 on Billboard's best-selling pop albums chart. The bassist Richard Davis, who played on the first Cadence LPs, moved to New York with Shirley in 1954 and worked with him until 1956. Through the late 1950s and 1960s Shirley recorded many albums for Cadence, setting standards, show tunes, folk songs and spirituals in a classical style with jazz harmony and rhythm. In 1961 his single "Water Boy" reached No. 40 on the Billboard Hot 100 and stayed on the chart for 14 weeks. At Basin Street East in New York, Duke Ellington heard him play, and the two became friends.

The group that carried his name for most of those years was the Don Shirley Trio, built around piano, cello and double bass. Discogs lists its regular members as Shirley, the bassist Ken Fricker and the Estonian cellist Jüri Täht. Shirley and Fricker had already recorded together on Don Shirley with Two Basses, which paired Fricker with a second bassist, Jimmy Bond. After the Cadence years he made albums for Columbia, including Water Boy (1965), The Gospel According to Don Shirley and Don Shirley in Concert (both 1969), and for Atlantic, where The Don Shirley Point of View appeared in 1972. In the concert hall he played Tchaikovsky's first piano concerto with the Detroit Symphony in late 1968, worked with the Chicago Symphony and the National Symphony Orchestra, and appeared as soloist at La Scala in Milan in a program of George Gershwin's music. As a composer he wrote organ symphonies, piano concertos, a cello concerto, three string quartets, a one-act opera, a symphonic poem based on James Joyce's Finnegans Wake, and a set of variations on Offenbach's Orpheus in the Underworld. Igor Stravinsky was among his admirers.

During the 1960s Shirley toured the United States, including the Deep South, believing his performances could change minds. For his first tour, in 1962, he hired Tony "Lip" Vallelonga, a New York nightclub bouncer, as driver and bodyguard. That story was dramatized in the 2018 film Green Book, named for the travel guide for Black motorists in the segregated United States, with Mahershala Ali playing Shirley. The film won the Academy Award for Best Picture at the 91st Academy Awards in 2019, and Ali won Best Supporting Actor. It also drew objections from Shirley's family. The film shows him estranged from his relatives and from other Black Americans; his surviving family says he was involved in the Civil Rights Movement, marched at Selma in 1965, knew other Black artists and leaders, and stayed in touch with his three brothers. His brother Maurice said Shirley never regarded Vallelonga as a friend but as an employee, his chauffeur. Against that, audio from the 2010 documentary Lost Bohemia has Shirley saying he trusted Vallelonga implicitly and that the two never had an employer and employee relationship, and Vallelonga's son Nick, the film's co-writer, said Shirley had approved what went into the script and had told him not to speak to other people. Jüri Täht was surprised to see a version of himself, a Russian character named Oleg, in a film about his employer, since he is an Estonian whose family had fled the Soviet Union. The author David Hajdu, who knew Shirley in the 1990s, wrote that the man he met was far more earthy, mercurial and exacting than the character on screen. According to Edwin Shirley III, Mahershala Ali phoned him to apologize and said he had not known there were close relatives he could have consulted.

Don Shirley passed away on April 6, 2013, at the age of 86, of heart disease.

Shirley's records set pop standards, show tunes, folk songs and spirituals in the language of a concert pianist: full chordal textures, classical-style variation and development, and a jazz sense of harmony and swing. The piano-cello-bass trio gave the music a chamber quality that few jazz groups of the period had, and the Cadence albums mix solo piano, duo with bass and trio. He sat between categories and the industry never settled where to file him. AllMusic lists him under mainstream jazz, cool and chamber jazz, with spirituals, gospel and standards as further styles. The closest jazz labels are Crossover Jazz, Chamber Jazz and Third Stream, but much of his career lay outside jazz: concerto performances with major orchestras, concert-hall compositions, religious and gospel records, and a pop chart single. The author David Hajdu, who knew him, described him as exacting and intolerant of imperfection in music.