James Hubert "Eubie" Blake was born February 7, 1887, in Baltimore, Maryland, the only one of his parents' children to survive infancy. Both John Sumner Blake, a dockworker, and Emily "Emma" Johnston Blake had been born enslaved. At five or six he was caught picking out melodies on an organ in a Baltimore music store; his parents bought him a $75 pump organ on a 25-cents-a-week installment plan, and at seven he began formal lessons with a neighborhood church organist, Margaret Marshall. By his teens he was playing piano professionally and illicitly, working a Baltimore bordello without his mother's knowledge, and by 1907 he had a standing winter engagement at boxer Joe Gans's Goldfield Hotel, spending summers in Atlantic City and studying composition locally with Llewellyn Wilson. He later said he composed his first rag, eventually titled "Charleston Rag" (also known as "Sounds of Africa"), around age 16, which would place it in 1903; he did not write it down until 1915 and did not record it until 1917. Sources disagree on this point, some giving 1899 at age 12, and the profile follows the later, better-documented date rather than repeating the earlier one uncritically.

Blake worked with James Reese Europe's Clef Club musicians in New York in the early 1910s and, in 1915, met the singer and lyricist Noble Sissle at a Baltimore hotel where both were performing. They formed a vaudeville act, the Dixie Duo, playing piano-and-voice on the black vaudeville circuit as one of the few such acts to work without the burnt-cork makeup still standard for Black performers at the time. World War I split them: Sissle enlisted and became drum major and a featured vocalist in Europe's 369th Infantry "Hell Fighters" Band, while Blake stayed stateside, touring the Keith circuit through 1918 and 1919 in a new act with the singer, drummer and comedian Broadway Jones. A surviving publicity photograph of "Broadway Jones' Famous Jazz Trio," Blake at the piano, dates from about 1918; the two men did not reach a recording studio together until a decade later, cutting "House Rent Lizzie" and "Dissatisfied Blues" for Victor on December 3, 1929. Blake's own first studio sides, cut in 1917 for Pathe as the Eubie Blake Trio ("Hungarian Rag"/"American Jubilee" and "Sarah From Sahara"/"Bunch of Blues"), predate both of those Broadway Jones dates.

Sissle and Blake reunited after the war, and their vaudeville act grew into a full production with the comedy team of Flournoy Miller and Aubrey Lyles, whose book and sketches became the show. Shuffle Along opened May 23, 1921, at the 63rd Street Music Hall on a shoestring budget, orchestra pit included, and ran 504 performances, an unusually long run for its era. It is generally credited as the first hit Broadway musical written, composed, directed and largely performed by Black artists, and the first to seat Black patrons in the orchestra section rather than confining them to the balcony. Its songs, above all "I'm Just Wild About Harry" and "Love Will Find a Way," became standards; "Harry" was later adopted, without permission, as Harry Truman's 1948 presidential campaign song. The chorus line launched Josephine Baker, who was turned away at her first audition as too young and too dark-skinned before joining the touring company and eventually the Broadway cast, and it featured Florence Mills and Adelaide Hall in more prominent roles. Sissle and Blake's own Victor sides as performers date mostly from this period, including "Baltimore Buzz" and "Bandana Days," cut July 15, 1921, with the show's pit band billed as the Shuffle Along Orchestra.

The partners wrote two further shows together, Elsie (1923) and The Chocolate Dandies (1924), toured England in 1926 to strong reviews, and made three short sound-on-film pieces for Lee de Forest's Phonofilm process in 1923, among the earliest surviving film footage of Black musical performers. When Sissle returned to London alone in 1927, for a solo act, the partnership lapsed (the pair had played London's Kit Kat Club together in 1926 and come back to the States that August; Sissle's own Paris band followed only in the summer of 1928); Blake resumed working with Broadway Jones through the Depression, including an extended run at the Royal Poinciana Hotel in Palm Beach, and the two split for good around 1932 or 1933 as bookings dried up. Sissle and Blake reunited once more, unsuccessfully, for the Depression-era flop Shuffle Along of 1933. Blake's most durable song from this stretch came from a different partnership: "Memories of You," written with lyricist Andy Razaf for Lew Leslie's Blackbirds of 1930, was recorded by Duke Ellington's Cotton Club Orchestra, with vocalist Dick Robertson, on October 2, 1930, alongside two more songs from the same score, "You're Lucky to Me" and "That Lindy Hop." It has been recorded by dozens of jazz artists since.

Blake married Avis Lee, a childhood acquaintance from Baltimore, in 1910; she died of tuberculosis in 1938. During World War II he toured with the USO, sometimes alongside Sissle, and met Marion Grant Tyler, a violinist's widow who became his second wife in 1945 and, afterward, his business manager. He largely retired from performing in 1946 and enrolled at New York University to study the Schillinger system of composition, graduating in about two and a half years and spending much of the next two decades transcribing, for the first time, music he had only ever played from memory. The turn came in 1969 with The Eighty-Six Years of Eubie Blake, a two-LP Columbia set produced by John Hammond from sessions recorded between December 1968 and March 1969; it returned Blake to The Tonight Show and The Merv Griffin Show, and the Library of Congress added it to the National Recording Registry in 2006. A steady run of ragtime-revival dates followed, including Golden Reunion in Ragtime (1962, with fellow veterans Joe Jordan and Charley Thompson) and Wild About Eubie (1977, with William Bolcom and Joan Morris), before the retrospective revue Eubie! opened on Broadway at the Ambassador Theatre on September 20, 1978, ran 439 performances and drew three Tony nominations, including one for Blake's own score. He made a cameo in the 1977 television movie Scott Joplin and appeared with Gregory Hines on Saturday Night Live on March 10, 1979.

Honors accumulated fast in his last decade: honorary doctorates from Rutgers, the University of Maryland, Howard University and other institutions; the George Peabody Medal from Johns Hopkins in 1980; and, on October 9, 1981, the Presidential Medal of Freedom from Ronald Reagan. In mid-December 1982 the Kennedy Center taped a televised tribute, Eubie Blake: A Century of Music, arranged by pianist Dick Hyman and featuring Rosemary Clooney, Cab Calloway, Joe Williams, Billy Taylor and Gregory Hines; it aired, and won an Emmy, after Blake's death. That distinction is worth stating precisely, because it is often blurred with the separate Kennedy Center Honors, which Blake never received. Blake had for decades claimed 1883 as his birth year, and the claim was widely repeated, including in his own obituaries; government records made public after his death (the 1900, 1910 and 1920 censuses, his 1917 draft card, and a 1920 passport application with his mother's sworn affidavit) all give 1887. He passed away at his Brooklyn home on February 12, 1983, of complications from pneumonia, five days after events billing it as his 100th birthday, which was in fact his 96th; even the New York Times obituary headline repeated the "100th birthday" claim. He was cremated and interred at Cypress Hills Cemetery in Brooklyn, under a headstone carrying the musical notation for "I'm Just Wild About Harry."

Blake's playing sat at the hinge between ragtime and stride: a hand span reported to cover a twelfth let him carry ragtime's structured, sectional left hand into looser, more syncopated territory, and pieces such as "Charleston Rag" and "Troublesome Ivories" push past strict ragtime form into the freer rhythmic feel that James P. Johnson and Fats Waller would later formalize as stride. Contemporaries and biographers describe an idiosyncratic vocabulary of "Eubieisms," rhythmic figures and voicings too particular to reduce cleanly to standard notation, which is part of why the piano rolls he cut from 1917 onward matter as much as his sheet music: they preserve interpretive detail that published scores simplified away for amateur pianists. As a songwriter his catalog runs through the vocabulary of Black musical theater into the mainstream popular song, with "I'm Just Wild About Harry" and "Memories of You" both becoming standards recorded far outside jazz, and Shuffle Along is credited with helping move syncopated, blues-inflected Black musical idioms into Broadway's mainstream at a moment when jazz itself was just beginning to be recorded. His late-career visibility, sustained from 1969 to his death, made him a direct link for younger musicians and audiences back to ragtime's first generation; pianist Ehud Asherie recorded an entire solo album, Shuffle Along (2016, Blue Heron Records), drawn from the score.