Eddie Harris was born in Chicago on October 20, 1934. His father was from Cuba and his mother from Mississippi. He studied music under Captain Walter Dyett at DuSable High School, which also trained Nat King Cole, Johnny Griffin, Clifford Jordan, Gene Ammons, and Julian Priester, and went on to Roosevelt University, where he was already proficient on piano, vibraphone, and tenor saxophone. While still in college he worked professionally with Ammons. His official site adds that he sang in Chicago Baptist churches as a boy and began piano lessons at about age three with a cousin.

Drafted into the United States Army, he was accepted while serving in Europe into the 7th Army Band, whose members also included Don Ellis, Leo Wright, and Cedar Walton. After his discharge he worked in New York City, returned to Chicago, and signed with Vee-Jay Records. His first Vee-Jay album, Exodus to Jazz, was recorded on January 17, 1961, at Universal Recording in Chicago with pianist Willie Pickens, guitarist Joe Diorio, bassist Bill Yancey, and drummer Harold Jones. It opened with his own jazz arrangement of Ernest Gold's theme from the film Exodus. A shortened version of that track, built on his playing in the upper register of the tenor saxophone, was heavily played on radio and became the first jazz record certified gold; the single entered the Billboard Hot 100 and reached No. 16 on the R&B chart. More Vee-Jay albums followed quickly, among them Mighty Like a Rose (recorded April 14, 1961), A Study in Jazz (1962), and Bossa Nova (recorded in New York in November 1962 with pianist and arranger Lalo Schifrin and guitarist Jimmy Raney).

He moved to Columbia Records in 1964 and made Cool Sax, Warm Heart (January 15 and 16, 1964), with Wynton Kelly on piano for four tracks, and Cool Sax from Hollywood to Broadway (September 22 to 24, 1964), with Walton, bassist Bob Cranshaw, and guitarist Kenny Burrell on two tracks. In 1965 he signed with Atlantic Records, where he re-established himself. The In Sound, recorded on August 9 and 30, 1965, and produced by Nesuhi Ertegun, paired him with Walton, bassist Ron Carter, drummer Billy Higgins, and trumpeter Ray Codrington, and won back many of his detractors with a bop program. It also holds the first recording of his composition "Freedom Jazz Dance," which the quintet of Miles Davis recorded for Miles Smiles in October 1966, adding extra bars between the phrases of the melody; the tune became a jazz standard.

From the mid-1960s Harris turned to electricity. On Mean Greens (recorded in March and June 1966) he played electric piano, and the album carries the first version of his "Listen Here." He also took up the Varitone, a woodwind pickup and effects unit that Selmer marketed from 1967. The Electrifying Eddie Harris, recorded on March 20, 1967, and released in early 1968, reached No. 2 on Billboard's R&B album chart. Its second track, "Listen Here," stretched to more than seven minutes on the album and was issued as a two-part single that climbed to No. 11 on the R&B chart and No. 45 on the Hot 100, and the album drew a Grammy nomination for best instrumental jazz performance by a small group or soloist with a small group. He followed it with Plug Me In (March 1968), with a horn section, and Silver Cycles (September and December 1968), with brass, strings, singers including Melba Moore and Valerie Simpson, and Joe Zawinul on piano for one track.

On June 21, 1969, Harris joined the pianist and singer Les McCann at the Montreux Jazz Festival with trumpeter Benny Bailey, bassist Leroy Vinnegar, and drummer Donald Dean. The musicians had not been able to rehearse, and the tapes, made by the festival's organizers, were passed to Atlantic for a fee of less than $100. Released as Swiss Movement, with McCann singing Gene McDaniels's "Compared to What," the album reached No. 1 on Billboard's jazz album chart, No. 2 on the R&B chart, and No. 29 on the pop LP chart, drew a Grammy nomination, and became one of the best-selling jazz albums of all time. The pair made a follow-up, Second Movement, on January 25, 1971, with guitarist Cornell Dupree, drummer Bernard Purdie, and a vocal group including Cissy Houston, and on March 6, 1971, they were among the American acts who played the Independence Day concert in Accra, Ghana, that became the film Soul to Soul.

In the 1970s Harris moved from Chicago to Los Angeles. From 1970 to 1975 he experimented with instruments of his own invention: the reed trumpet, a trumpet fitted with a saxophone mouthpiece, which he first played at the 1970 Newport Jazz Festival; the saxobone, a saxophone with a trombone mouthpiece; and the guitorgan, a combination of guitar and organ. The Chicago sessions that produced Instant Death (December 7, 1971) and Eddie Harris Sings the Blues (July 25, 1972) used a band of Muhal Richard Abrams, guitarist Ronald Muldrow, and bassist Rufus Reid, who spent five years with Harris according to Reid's own profile. He also sang comic blues and rhythm and blues, on records such as That Is Why You're Overweight (1976) and the live The Reason Why I'm Talking S--t (1975), and made the rock-flavored E.H. in the U.K. in London in 1973 with Steve Winwood, Jeff Beck, Albert Lee, Chris Squire, and Ian Paice among the players. He left Atlantic after a final album there in 1977, after more than twelve years, and recorded two albums for RCA, I'm Tired of Driving (1978) and Playin' with Myself (1980).

The rest of his career was spent largely on small and independent labels, including SteepleChase (Steps Up, recorded in Copenhagen on February 20, 1981, with pianist Tete Montoliu), Chiaroscuro, Timeless, and Enja. He also appeared as a guest soloist: with Horace Silver on the Spiritualizing the Senses (January 1983) and There's No Need to Struggle (August and September 1983) sessions for Silver's Silveto label, with pianist Horace Parlan on Glad I Found You (1984), with Buddy Montgomery on Ties of Love (1987), and with John Scofield on Hand Jive (recorded in October 1993). Late guest spots included Etta James's Time After Time (1995), and a session with Jimmy Smith recorded in 1981 was released as All the Way Live in 1996. According to his official site he made more than 70 albums, wrote seven music books, and held a patent for a reed mouthpiece for brass instruments. Harris passed away in Los Angeles on November 5, 1996, at the age of 62. The Last Concert appeared on ACT in 1997, and Seamus Blake recorded an organ-band tribute, The Electrifying Seamus Blake Plays the Music of Eddie Harris: EH!, with Sam Yahel in November 2025.

Harris began as a cool-toned tenor player whose biggest debt, in AllMusic's reading of his early Vee-Jay records, was to Stan Getz's bop recordings, with touches of soul jazz, and a 2006 thesis on his improvisation by Johnny Lippiett found a bebop base and a distinctive use of fourth intervals. He also wrote instructional books, among them The Intervallistic Concept, published by Charles Colin. His tenor playing often went into the highest register of the instrument, which gave "Exodus" its hook, and he later ran the saxophone through the Varitone and moved between jazz and rhythm and blues audiences, an approach that critics divided over: Harvey Pekar called Swiss Movement cliché-ridden in DownBeat, while Richie Unterberger of AllMusic ranked it among the best soul jazz albums ever made. He played electric piano and organ as well, built horns of his own in the 1970s, and added comic vocals such as "Eddie Who?" and "That Is Why You're Overweight." His compositions have outlasted the novelties: "Freedom Jazz Dance" is played widely as a standard, and "Listen Here" has been recorded by many other musicians.