Widely renowned as the leading exponent of rag music on the East Coast, Eubie Blake began studying music (specifically the Estey organ) at age six. He composed his first rag, The Charleston Rag, in 1899, although it was not published until years later. His major published and unpublished rags include Chevy Chase (1914), Fizz Water (1914), Bugle Call Rag (1926), Eubie's Boogie, Troublesome Ivories, and Brittwood Rag. In 1915 Blake met Noble Sissle and began one of the most influential and successful partnerships in music history.

Sophie Tucker sang the team's first song, It's All Your Fault, which became a smash hit. In 1920 they were approached by Flournoy Miller and Aubrey Lyles to compose Shuffle Along, which sparked a new era in African American musical theater. Shuffle Along opened in 1921 and ran for 504 performances, launching the careers of Josephine Baker, Florence Mills, Catherina Jarboro, Paul Robeson, and Adelaide Hall. The show's most famous songs included I'm Just Wild About Harry, Bandana Days, and Love Will Find a Way. Originally planned for a black audience, the show ran two weeks at the Howard Theatre in Washington D.C. and at the Dunbar Theatre in Philadelphia, before opening at New York City's 63rd Street Music Hall on May 23, 1921. It closed with a reported gross of eight million dollars. Blake once described the opening of Shuffle Along as the proudest day of his life. Undoubtedly Shuffle Along's role in changing the history of musical theater in America contributed to Blake's pride: although the balcony remained the segregated "black only" space that historically characterized Broadway theaters, Shuffle Along marked the first time in Broadway history that black patrons were allowed to sit in the orchestra and other sections traditionally reserved for whites. Black patrons were, Variety Magazine noted, "as far front as the fifth row."⁶⁵ After Shuffle Along, Blake earned $250 a week with the 1930 production of Lew Leslie's Blackbirds, billed as "Glorifying the American Negro." Lew Leslie's Blackbirds brought Blake together with famed lyricist Andy Razaf.

During World War II Blake served as musical director with several U.S.O (United Service Organization) tours. In the late 1940s he went into retirement and studied the Schillinger System of Music at the University of New York. The ragtime "Scott Joplin" revival of the 1950s brought renewed interest in Blake's music. In 1968 music impresario John Hammond organized a session for Blake which brought forth the 1969 two-album recording The Eighty-Six Years of Eubie Blake. That same year he played a successful concert at the Newport Jazz Festival. In 1971 Blake launched his own record company, Eubie Blake Music Inc. During the 1970s he was awarded honorary degrees from such distinguished institutions as Dartmouth College, Rutgers University, and the New England Conservatory. In 1976 he provided the introduction for Terry Waldo's book, This is Ragtime. Blake's legendary music was made familiar to new audiences in 1979, with the opening of a revue of his music on Broadway. Eubie! was the hit of the 1979 season. In 1981 he received the Presidential Medal of Freedom. Suffering from pneumonia, Blake was unable to attend several celebrations held in his honor of his 100th birthday. He was, however, able to attend a Kennedy Center tribute in honor of his 100th birthday, which included performances from Phyllis Hyman, Patti Labelle, Stevie Wonder, Rosemary Clooney, and Cab Calloway. He died in New York on February 12, 1983⁶⁶.