John Cornelius Hodges was born on July 25, 1907, in the Cambridgeport neighborhood of Cambridge, Massachusetts, to John H. Hodges and Katie Swan Hodges, who both came from Virginia. After a short stay in North Cambridge the family settled on Hammond Street in Boston's South End, where he grew up alongside the future saxophonists Harry Carney, Charlie Holmes and Howard E. Johnson. His first instruments were drums and piano. His mother was a capable pianist, he was largely self-taught, and as a teenager he earned $8 a night playing piano at dances in private homes. By his teens he had taken up the soprano saxophone, and around the same time he acquired the nickname Rabbit, which people attributed either to his speed as a sprinter or, in Carney's version, to the way he nibbled lettuce and tomato sandwiches.

At fourteen he went with his eldest sister to see Sidney Bechet in Jimmy Cooper's Black and White Revue at a Boston burlesque house. His sister introduced them, Bechet asked the boy to play the soprano saxophone he had brought along, and Hodges performed "My Honey's Lovin' Arms." Bechet encouraged him and gave him formal lessons. Hodges built a local reputation and was working in New York by 1924. In the mid-1920s he played in bands led by Bobby Sawyer, Lloyd Scott, Chick Webb (from late 1926, at the Paddock Club and the Savoy Ballroom) and Luckey Roberts, and he followed Bechet into Willie "The Lion" Smith's quartet at the Rhythm Club, according to All About Jazz. When Duke Ellington set out to enlarge his orchestra in 1928, his clarinetist Barney Bigard recommended Hodges, who joined that year.

Hodges played lead alto in Ellington's saxophone section and was the orchestra's most featured soloist for the next four decades. Ellington wrote showcases for him, including "Confab with Rab," "Jeep's Blues," "Sultry Sunset" and "Hodge Podge," and the ballads tied to his name include "Warm Valley," "Passion Flower," "In a Sentimental Mood," "Prelude to a Kiss," "I Got It Bad (and That Ain't Good)" and "Blood Count." Among the faster pieces he was featured in "Things Ain't What They Used to Be" and "The Jeep Is Jumpin'." From 1937 he also led small studio groups drawn from the orchestra for Victor and other labels. He was one of the Ellington players who took part in Benny Goodman's 1938 Carnegie Hall concert, and Goodman called him the greatest alto saxophonist he had ever heard. After 1940 he stopped playing the soprano saxophone altogether, and through the 1940s he regularly won the readers' polls run by Down Beat, Metronome and Esquire.

In March 1951, to the surprise of the jazz public, Hodges left Ellington to form his own band, taking trombonist Lawrence Brown and drummer Sonny Greer with him. The first sessions produced his one hit, "Castle Rock," a tune by the group's tenor saxophonist Al Sears; AllMusic points out that the record belongs more to Sears's tenor than to Hodges. His records for Norman Granz's Norgran label followed, and the young John Coltrane played in the band in 1953 and 1954, appearing on the sessions for Used to Be Duke. The band struggled and broke up in the spring of 1955. After a short stretch of television work on The Ted Steele Show, Hodges rejoined Ellington in August 1955 and stayed with him for the rest of his life, apart from a few brief absences.

His return came just before the orchestra's revival at the 1956 Newport Jazz Festival, where Ellington introduced him to the crowd and he played "I Got It Bad" and "Jeep's Blues." He is the alto voice on Such Sweet Thunder (1957) and the Anatomy of a Murder soundtrack (1959). Away from the band he led a steady run of small-group dates for Norgran and then Verve, often with Ellington men, among them Duke's in Bed (1956), Blues-A-Plenty (1958), the two albums co-billed with Ellington, Back to Back and Side by Side (1959), and Gerry Mulligan Meets Johnny Hodges (1959). Between 1961 and 1967 he made eight albums with the organist Wild Bill Davis. He also recorded with Coleman Hawkins and Roy Eldridge at the Village Gate in 1962, with the pianist Earl Hines in 1966 and 1967, and in 1965 on an album of standards with Lawrence Welk's orchestra.

His last concerts were at the Imperial Room in Toronto. He passed away on May 11, 1970, in New York City, of a heart attack suffered during a visit to a dentist's office. His final recordings are on Ellington's New Orleans Suite, which was only half finished when he died. Ellington said afterward that the band would never sound the same without him. Hodges was married twice. He and his first wife, Bertha Pettiford, had a daughter, and he and his second wife, Edith Cue, had a son, John C. Hodges II, and a daughter, Lorna Lee.

Hodges was known for a tone that musicians and critics from every school singled out for its beauty, and for his handling of ballads and blues. He used a wide vibrato and sliding portamento, gliding between notes the way a trombone does, and he favored economy over display: the effect came from sound and time, not from the number of notes. His basic style barely changed across four decades, and in later years he stayed closer to the melody on ballads and played short, pointed riffs on the faster pieces, many of them blues. Sidney Bechet was his one major teacher and model. In turn he was widely copied: John Coltrane named him his first model on the saxophone, Ben Webster counted him a major influence during their years together in Duke Ellington's band, and Charlie Parker likened him to the opera soprano Lily Pons. The alto saxophonists Lee Konitz, Phil Woods, Hank Crawford and Dmitry Baevsky have each cited him as an influence, Lou Donaldson's rounded ballad tone has been compared with his, and Owen Broder devoted two albums to his repertoire (Hodges: Front and Center, 2022 and 2024). Along with Benny Carter he is regarded as one of the definitive alto saxophonists of the big band era. He played a Conn 6M in the 1940s, later a Buescher 400, and by the late 1960s a silver-plated Vito Leblanc Rationale. He is a member of the DownBeat Jazz Hall of Fame.