Leslie Coleman McCann was born on September 23, 1935, in Lexington, Kentucky, the son of James and Anna McCann, and grew up in a musical family of five children who sang in the church choir at Shiloh Baptist. He played tuba and drums in his school marching band and was largely self-taught on piano, having had only a few weeks of lessons at the age of six before his teacher died. At 17 he joined the U.S. Navy, won a Navy talent contest as a singer, and appeared on The Ed Sullivan Show as a result. After his discharge he settled in Los Angeles, studied at Los Angeles City College, and hosted a Monday-night jam session at the Hillcrest Club, where he met the singer and songwriter Gene McDaniels. His trio's first job, at the Purple Onion in 1959, was accompanying McDaniels, and he turned down an offer to join Cannonball Adderley's band so that he could build his own group.

A Pacific Jazz representative heard him play and offered him a contract, and from 1960 to 1964 he recorded more than a dozen albums for the label, most of them as Les McCann Ltd. with bassist Leroy Vinnegar and drummer Ron Jefferson, and later with bassist Herbie Lewis. The debut, Les McCann Ltd. Plays the Truth (1960), was followed by Les McCann Ltd. in San Francisco, taped at the Jazz Workshop in December 1960, and by Les McCann Ltd. Plays the Shampoo, recorded in 1961 during a New York residency and issued in 1963, whose title tune became an early hit. The trio also backed the singer Lou Rawls on his Capitol debut, Stormy Monday (1962), and McCann played on sessions led by Teddy Edwards, organist Richard "Groove" Holmes, and saxophonist Stanley Turrentine. In 1963 he toured Europe with guitarist Charlie Byrd and tenor saxophonist Zoot Sims, according to Byrd's profile. Jazz Waltz (recorded in 1963) paired the trio with the Jazz Crusaders, and in the mid-1960s he also recorded for Limelight, including Les McCann Plays the Hits (1966), on which he sang a slow version of McDaniels's protest song "Compared to What."

He moved to Atlantic in the late 1960s, and his first album for the label, Much Les (recorded in 1968, released in 1969), added strings and Latin percussionists, among them Willie Bobo on timbales, to the trio of McCann, Vinnegar, and drummer Donald Dean. In 1968 he heard the singer Roberta Flack in Washington and arranged an audition for her with Atlantic producer Joel Dorn, which led to her signing; he later wrote liner notes for her debut album, First Take. On June 21, 1969, at the Montreux Jazz Festival in Switzerland, he played an unrehearsed set with saxophonist Eddie Harris, trumpeter Benny Bailey, Vinnegar, and Dean. The festival's organizers recorded it, and Atlantic took the tapes for a fee of less than $100 and issued them as Swiss Movement. McCann sang "Compared to What" on it, the single sold more than a million copies, and the album reached number one on Billboard's jazz album chart and was nominated for a Grammy Award. He and Harris recorded a follow-up, Second Movement, in January 1971, and on March 6, 1971, both played in the 14-hour concert in Accra, Ghana, before more than 100,000 people that was filmed as Soul to Soul.

After Swiss Movement McCann, who had been known mainly as a pianist, put more weight on his singing, and through the early 1970s he moved toward electric keyboards and studio experiment. Invitation to Openness (recorded in 1971, released in 1972) is three long pieces with Yusef Lateef, guitarist Cornell Dupree, and drummers Alphonse Mouzon and Bernard Purdie, with McCann on piano, electric piano, and Moog synthesizer. Talk to the People (1972) included a cover of Marvin Gaye's "What's Going On." Layers (recorded in 1972, released in 1973) is almost entirely electronic apart from a bassist and three percussionists and includes "Sometimes I Cry." The double album Live at Montreux (recorded in 1972, issued in 1973) features Rahsaan Roland Kirk on two tracks. Another Beginning (1974) added horns and strings, and he continued on Atlantic until 1976, then recorded for ABC/Impulse! (1977), A&M (1978 and 1979), and smaller labels through the 1980s.

McCann had a stroke in the mid-1990s that slowed his work, and he returned to the studio with Pump It Up (2002), continuing to release music until 2018. He also exhibited his work as a painter and photographer, and a collection of his photographs from 1960 to 1980 was published as Invitation to Openness: The Jazz & Soul Photography of Les McCann in 2015. In August 2023 the pianist Joe Alterman, a friend and protege, released Joe Alterman Plays Les McCann: Big Mo & Little Joe, a tribute album that closes with a song the two wrote together. McCann passed away in a Los Angeles hospital on December 29, 2023, at the age of 88, after being admitted with pneumonia. His recordings have been sampled by nearly 300 hip-hop acts, among them A Tribe Called Quest, De La Soul, the Notorious B.I.G., and Nas.

McCann is known for his innovations in soul jazz: a gospel- and blues-rooted trio style in the early 1960s, then an Atlantic-era blend of jazz with funk, soul, and world rhythms that made early use of the electric piano, clavinet, and synthesizer, and a soulful, hollering vocal delivery that he often aimed at songs of social comment. AllMusic's review of Layers calls it one of the first jazz albums built so completely on electronic keyboards. Swiss Movement was dismissed as cliche-ridden by DownBeat's Harvey Pekar when it appeared, but AllMusic's Richie Unterberger later named it one of the most popular soul jazz albums of all time. George Duke named McCann, along with Cal Tjader, as one of his key early influences, according to Duke's profile, and McCann's grooves, including "Sometimes I Cry" from Layers and "Compared to What," have been reused by hip-hop and electronic producers for decades, in Slick Rick's "Behind Bars" and Massive Attack's "Teardrop," among other records.