Edgar "Eddie" Jefferson was born August 3, 1918, in Pittsburgh, Pennsylvania. His father worked in show business, and Jefferson started early as a dancer, teaming up as half of the Jefferson-Taylor duo on the Black vaudeville touring circuit of the 1930s and 1940s, sharing bills with swing and early bebop musicians including Coleman Hawkins. It was during those years on the road, listening obsessively to records backstage, that he began writing lyrics to recorded instrumental solos by Lester Young, Herschel Evans, Buddy Tate, and Chu Berry, a practice he later credited singer Leo Watson with inspiring. By the late 1940s Jefferson had shifted from dancing to singing his lyric-set solos in clubs, effectively inventing vocalese as a distinct jazz vocal style.

His best-known piece of writing began with a saxophone solo, not a song. In 1949, in Stockholm, saxophonist James Moody recorded an improvisation on "I'm in the Mood for Love" that Jefferson set new lyrics to and began performing around New York clubs. Singer King Pleasure heard him do it, won the Apollo Theater's amateur night with the same words in November 1951, and recorded it for Prestige in 1952; the record became a hit under the title "Moody's Mood for Love" and made Pleasure's name, while Jefferson, its actual lyricist, went unrecognized by the wider public for years (Moody himself did not learn who had really written the words until later). Jefferson recorded his own version in 1957, a single credited "Eddie Jefferson With James Moody and His Orchestra" on Checker, by which point he had already spent five years cutting scattered 78s and 45s of vocalese pieces for small labels, going back to 1952's "The Birdland Story" and "I Got the Blues."

Jefferson's first album under his own name, Letter From Home, did not arrive until 1962, recorded for Riverside across sessions in the winter of 1961-62 with an unusually large supporting cast arranged by Ernie Wilkins: James Moody, Johnny Griffin, Clark Terry, Wynton Kelly, Joe Zawinul, Sam Jones, and Louis Hayes among them. Two Prestige albums followed later in the decade, both produced by Don Schlitten and both leaning on Detroit pianist Barry Harris: Body and Soul (1968), with James Moody again on tenor, and Come Along With Me (1969), featuring alto saxophonist Charles McPherson. A third Prestige-era recording, cut in 1965 but not released until 1976 as The Jazz Singer, sat on the shelf for eleven years.

The mid-1970s brought Jefferson his most visible late-career partnership, with the young alto saxophonist Richie Cole. The two began recording together on 1974's Things Are Getting Better (Muse) and were soon co-leading a touring group, documented on Still on the Planet (1976) and The Main Man (1977, featuring Billy Hart and George Duvivier). Jefferson kept working outside that partnership too: in 1973 he wrote and sang lyrics on two tracks of drummer Roy Brooks's Ethnic Expressions, and in July 1976 he sang a live date at Ali's Alley, the Soho loft club drummer Rashied Ali had built and ran out of his own apartment, backed by Ali's working quintet; the tapes surfaced thirty years later as the posthumous release Eddie Jefferson At Ali's Alley (2009). In 1979, in Paris, he sang on Frank Wright's Kevin, My Dear Son alongside drummer Philly Joe Jones. That year's live album with Cole's band, The Live-Liest, brought Jefferson his first and only Grammy nomination, for Best Vocal Jazz Performance.

Jefferson did not live to learn the outcome of that nomination. On the night of May 8, 1979, he finished a set with Richie Cole's band at Baker's Keyboard Lounge in Detroit and was shot in the parking lot as he left the club with Cole around 1:35 a.m.; he passed away from his wounds early the next morning, May 9, at age 60. A man named William Perryman, reportedly a dancer Jefferson had once fired from a gig, was arrested and charged with the murder within two days but was acquitted at trial, and no one else was ever convicted. Cole's Muse album Hollywood Madness, recorded with Jefferson before his death, was released the following year with additional guest vocal spots from Tom Waits and The Manhattan Transfer added afterward, a posthumous tribute to the partnership.

Jefferson is credited as vocalese's originator: rather than scatting wordlessly or singing a tune's original lyric, he set new, narrative words directly to note-for-note transcriptions of recorded instrumental solos, turning improvisations by Charlie Parker, James Moody, Miles Davis, John Coltrane, and others into sung stories. He named singer Leo Watson as his own formative influence, and his years as half of a professional dance act before he ever sang publicly shaped a rhythmic precision that let him track a horn player's exact phrasing rather than approximate it. His authorship of "Moody's Mood for Love" was overshadowed for years by King Pleasure's hit recording of it, a slight that became one of jazz's more persistent authorship disputes, but Jefferson's own influence outlived the dispute: The Manhattan Transfer built a 1979 vocal arrangement of "Body and Soul" around the Jefferson/Coleman Hawkins pairing, and George Benson's 1980 album Give Me the Night still carried a "Moody's Mood" songwriting credit in Jefferson's name, evidence that his lyrics kept circulating commercially even after his death.