John Aaron Lewis was born on May 3, 1920, in La Grange, Illinois. When he was two months old his mother, a trained singer, took him to Albuquerque, New Mexico, where she died of peritonitis when he was four, and his grandmother and great-grandmother raised him. He began piano lessons at seven, played in a family band and a Boy Scout music group, and heard jazz through an aunt who loved to dance. After Albuquerque High School he studied at the University of New Mexico, double majoring in anthropology and music, leading a small dance band, and studying piano with Walter Keller, whom he later honored in the title piece of the Modern Jazz Quartet's 1974 album In Memoriam. He entered the Army in 1942 and played with the drummer Kenny Clarke, who urged him to settle in New York once the war ended. Lewis moved there in 1945 and studied at the Manhattan School of Music, graduating with a master's degree in 1953.

Clarke brought Lewis into Dizzy Gillespie's bebop big band, and he won the job by playing a piece he had written for their Army band, which Gillespie renamed "Two Bass Hit." Lewis composed, arranged and played piano for the band from 1946 until 1948, including its European tour. He then recorded as an accompanist with Charlie Parker, on "Parker's Mood" (1948) and "Blues for Alice" (1951), and worked with Lester Young, Ella Fitzgerald and Illinois Jacquet. He also joined the 1949 nonet that Miles Davis led with arrangers Gil Evans and Gerry Mulligan, arranging "Move" and "Budo," writing "Rouge," and playing piano on the second session, on April 22, 1949; those sides later formed part of Birth of the Cool.

Within Gillespie's band, Lewis, vibraphonist Milt Jackson, Clarke and bassist Ray Brown played their own short sets while the horns rested. The four recorded as the Milt Jackson Quartet for Gillespie's Dee Gee label on August 18, 1951, and after Percy Heath replaced Brown on bass, the group was incorporated on January 14, 1952, as the Modern Jazz Society, with the Modern Jazz Quartet as its working band. Lewis was its musical director from the start. His first pieces for it, beginning with "Vendôme," recorded for Prestige on December 22, 1952, combined fugal counterpoint with improvisation, and "Django," a tribute to the guitarist Django Reinhardt recorded between 1953 and 1955, became its signature piece. Clarke left in January 1955 and was replaced by Connie Kay, who played on Concorde (July 2, 1955), the last of the group's Prestige albums. The quartet moved to Atlantic in 1956, made its first European tour that October, and became one of the first small jazz groups to play concert halls rather than nightclubs, dressed in formal clothes.

Alongside the quartet, Lewis became a central figure in what Gunther Schuller called Third Stream music. He founded the Jazz and Classical Music Society in 1955, which presented concerts at New York's Town Hall; was head of faculty at the Lenox School of Jazz in Massachusetts from 1957 to 1960; and was director of the Monterey Jazz Festival from 1958 to 1983. In 1962 he co-founded Orchestra U.S.A. with Schuller and Harold Farberman, a large ensemble with strings that recorded for Colpix, Columbia and RCA until 1965. He scored the film Sait-on jamais (released in English as No Sun in Venice, 1957), then Odds Against Tomorrow (1959), for which he assembled a 22-piece orchestra that included Jackson, Heath, Kay, Bill Evans and Jim Hall, followed by A Milanese Story (1962) and cues for Derek Jarman's The Tempest (1979). His own albums from these years included Grand Encounter (1956, with Bill Perkins, Hall, Heath and Chico Hamilton), Afternoon in Paris (with the French guitarist Sacha Distel), Improvised Meditations & Excursions (1959), Jazz Abstractions (recorded in December 1960, with music by Schuller and Hall), and European Encounter (1962, with the Danish violinist Svend Asmussen).

The Modern Jazz Quartet disbanded after a farewell concert in November 1974, when Jackson left, and Lewis taught at the City College of New York and at Harvard. A Japanese commission from CBS produced his first solo piano album, Statements and Sketches for Development (1976), and in Japan he also gave recitals with Hank Jones and Marian McPartland. The quartet reunited for a tour in 1981 and played together sporadically until it ended for good in 1997. In those years Lewis led a sextet, the John Lewis Group, and was the first bandleader of the American Jazz Orchestra, a repertory big band founded in New York by Gary Giddins and Roberta Swann in the mid-1980s. He recorded J. S. Bach's Well-Tempered Clavier preludes and fugues for Philips in four volumes between 1984 and 1989, with guitarist Howard Collins, bassist Marc Johnson and string players, and the Goldberg-variations-based The Chess Game with his wife, the harpsichordist Mirjana Lewis. Berklee College of Music gave him an honorary doctorate in 1989, and in 1992 he took part in the Re-birth of the Cool sessions with Mulligan. His last albums were the solo Evolution (1999) and Evolution II (recorded in 2000, released in 2001), both for Atlantic. After a final concert at Lincoln Center in January 2001, he passed away in New York City on March 29, 2001, of prostate cancer. He had been married for 39 years to Mirjana Lewis, who died in 2010, and they had a son and a daughter.

Lewis played with a spare, deliberate touch, often answering a soloist with simple counter-melodies in octaves rather than chords. He named the ensemble integration of Count Basie's band and the melodic improvising of Lester Young as his ideals, and he cited Duke Ellington's band as the model for the quartet's formal dress. To these he added the fugues and counterpoint of Bach, the clear textures of Stravinsky and the blues, balancing composed passages against improvised ones so that neither dominated. Critics have singled out his quartet pieces "Django," "Concorde," "Versailles" and "Vendôme" and the commedia dell'arte suites Fontessa and The Comedy, and the critic Francis Davis likened his reconciling of composition and improvisation to the achievements of Ellington and Jelly Roll Morton, while some bebop partisans found the music too polished. As a pianist he was mentioned in the same breath as Thelonious Monk and Ellington for his economy, and in the early 1980s he named Art Tatum, Hank Jones and Oscar Peterson among the pianists he listened to. Through the quartet, Orchestra U.S.A., the Lenox faculty and the Monterey Jazz Festival, he was among the most important figures in Third Stream and chamber jazz, and he taught jazz piano until late in life.