In 1921, he and his long-time collaborator Noble Sissle wrote Shuffle Along, one of the first Broadway musicals written and directed by African Americans.

[1] Blake's compositions included such hits as "Bandana Days", "Charleston Rag", "Love Will Find a Way", "Memories of You" and "I'm Just Wild About Harry".

Of the many children born to former slaves Emily "Emma" Johnstone and John Sumner Blake, he was the only one to survive childhood.

Census, military, and Social Security records and Blake's passport application and passport—uniformly give his birth year as 1887.

[12] In 1912, Blake began playing in vaudeville with James Reese Europe's Society Orchestra, which accompanied Vernon and Irene Castle's ballroom dance act.

Shortly after World War I, Blake formed a vaudeville musical act, the Dixie Duo, with performer Noble Sissle.

[13] Rudolf Fisher insisted that Shuffle Along "had ruined his favorite places of African-American sociability in Harlem" due to the influx of white patrons.

Its reliance on "stereotypical black stage humor" and "the primitivist conventions of cabaret," in the words of Thomas Brothers, made the show a hit, running for 504 performances with three years of national tours.

[17] In July 1910, Blake married Avis Elizabeth Cecelia Lee, proposing to her in a chauffeur-driven car he hired.

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.

[21][22] Eubie!, a revue featuring Blake's music, with lyrics by Noble Sissle, Andy Razaf, Johnny Brandon, F. E. Miller and Jim Europe, opened on Broadway in 1978.

Blake performed with Gregory Hines on the television program Saturday Night Live on March 10, 1979 (season 4, episode 14).

His headstone, engraved with the musical notation of "I'm Just Wild About Harry", was commissioned by the African Atlantic Genealogical Society.