Eubie Blake was born on February 7, 1887, in Baltimore, Maryland. Blake's musical training began when he was four or five years old. The Blakes purchased a pump organ for $75.00. When Blake was seven, he received music lessons from a neighbor, Margaret Marshall, an organist for the Methodist church. At age 15, without his parents' knowledge, he began playing piano at Aggie Shelton's Baltimore bordello. Blake got his first big break in the music business in 1907, when the world champion boxer Joe Gans hired him to play the piano at Gans's Goldfield Hotel. This was the first "black and tan club" in Baltimore. Blake played at the Goldfield during the winters from 1907-1914, spending his summers playing clubs in Atlantic City. During this period, he also studied composition in Baltimore with Llewellyn Wilson.
In 1912, Blake began playing in vaudeville with James Reese Europe's Society Orchestra, which accompanied Vernon and Irene Castle's ballroom dance act. The band played ragtime music, which was still quite popular. Shortly after World War I, Blake joined forces with the performer Noble Sissle to form a vaudeville musical act, the Dixie Duo. After vaudeville, the pair began work on a musical revue, Shuffle Along, which incorporated songs they had written, and had a book written by F. E. Miller and Aubrey Lyles. When it premiered in June 1921, Shuffle Along became the first hit musical on Broadway written by and about African-Americans. The musical also introduced hit songs such as "I'm Just Wild About Harry" and "Love Will Find a Way."
In 1923, Blake made three films for Lee de Forest in de Forest's Phonofilm sound-on-film process. These films are preserved in the Maurice Zouary film collection in the Library of Congress collection. He also appeared in Warner Brothers' 1932 short film Pie, Pie Blackbird with the Nicholas Brothers, Nina Mae McKinney, and Noble Sissle. That same year he and his orchestra provided most of the music for the film Harlem Is Heaven.
In July 1910, Blake married Avis Elizabeth Cecelia Lee, proposing to her in a chauffeur-driven car he hired. Blake brought his newlywed to Atlantic City, New Jersey, where he had already found employment at the Boathouse nightclub. In 1938, Avis was diagnosed with tuberculosis. She died later that year, at the age of 58. While serving as bandleader with the USO during World War II, he met Marion Grant Tyler, the widow of the violinist Willy Tyler. Blake and Tyler married in 1945. She was a performer and a businesswoman and became his valued business manager until her death in 1982.
In 1946, Blake retired from performing and enrolled in New York University, where he studied the Schillinger System of music composition, graduating in two and a half years. He spent the next two decades using the Schillinger System to transcribe songs that he had memorized but had never written down. In the 1970s and 1980s, public interest in Blake's music rekindled following the release of his 1969 retrospective album, The 86 Years of Eubie Blake.
Blake was a frequent guest of The Tonight Show Starring Johnny Carson and Merv Griffin. He was featured by leading conductors, such as Leonard Bernstein and Arthur Fiedler. In 1977, he played Will Williams in the Jeremy Kagan biographical film Scott Joplin. By 1975, he had been awarded honorary doctorates from Rutgers, the New England Conservatory, the University of Maryland, Morgan State University, Pratt Institute, Brooklyn College, and Dartmouth. On October 9, 1981, he received the Presidential Medal of Freedom, awarded by President Ronald Reagan.
Blake continued to play and record until his death, on February 12, 1983, in Brooklyn. He was buried in Cypress Hills Cemetery in Brooklyn, New York. The African Atlantic Genealogical Society commissioned his headstone, engraved with the musical notation of “I’m Just Wild About Harry”.