Boniface Ferdinand Leonard DeFranco was born on February 17, 1923, in Camden, New Jersey, and grew up in South Philadelphia. His father was a blind guitarist who earned his living tuning pianos; after teaching his son mandolin by ear, he bought him a $25 clarinet on the advice of musician friends, and DeFranco was playing it by the age of nine. He studied at the Mastbaum School of Music, a vocational school with a strong music course, and decided to play jazz after hearing the clarinetist Johnny Mince with Tommy Dorsey's band at the Earle Theater in Philadelphia. At fourteen he won a national Tommy Dorsey swing contest that was broadcast on the radio, and Dorsey told him afterward that he would play in the band someday. He also appeared on the Saturday Night Swing Club radio program with Gene Krupa.

After graduating from Mastbaum in 1939 he went on the road with the trumpeter Johnny "Scat" Davis, then played with Krupa in 1941 and with Charlie Barnet in 1942 and 1943. On tour with Barnet around 1943 he heard Charlie Parker's records with Jay McShann, and he decided to articulate on the clarinet the way Parker did on the alto saxophone. In 1944 he became a featured soloist with Dorsey, whose band he left and rejoined more than once; his solo on "Opus One" led to a DownBeat award in 1945, and in his own account Dorsey fired him once for objecting to repeating that solo note for note every night, then took him back a few months later on a compromise. He played with Boyd Raeburn's experimental orchestra in 1947, settled in New York in 1948, and took part in Metronome All-Star recording sessions, where he came to know Parker. The National Endowment for the Arts describes him as the first jazz clarinetist to make his mark in bebop. In 1949 he recorded modern-sounding sides for Capitol with a sextet and a big band, some of which were later issued alongside Lennie Tristano's 1949 Capitol recordings on the LP Crosscurrents.

In 1950 he joined Count Basie's small group for about a year, and in 1951 he formed a big band that dissolved in under twelve months. From 1952 to 1955 he led a touring quartet whose pianists were Kenny Drew and Sonny Clark, whose bassists included Eugene Wright, and whose drummers were Art Blakey and Bobby White. He recorded steadily for Norgran and Verve, the labels run by Norman Granz, and appeared on Jazz at the Philharmonic tours; he later said he learned more about rhythm from Blakey than from any other drummer, and that the racially mixed group drew complaints from some audiences on the road. In 1954 he toured Europe with Billie Holiday.

As bebop work dried up in the middle of the decade he moved to California, where he led a succession of small groups and played in studio orchestras conducted by Nelson Riddle. Granz paired him with Oscar Peterson for a Gershwin album recorded in December 1954 and for a 1957 quartet album, and with Art Tatum for a quartet session recorded on February 6, 1956, in Los Angeles. He recorded tribute albums to Benny Goodman and Artie Shaw for Verve in 1957 and 1958, and a septet date that included Herbie Mann, bassist Scott LaFaro and vibraphonist Victor Feldman became the live album Live Date!. For Dot he played Nelson Riddle's Cross Country Suite in 1958.

In 1960 he formed a quartet with the accordionist Tommy Gumina that explored polytonal writing drawn from Prokofiev, Shostakovich and film composers such as David Raksin; it recorded for Decca and Mercury between 1960 and 1964, a period he later described as a creative high point and a financial failure. In December 1964 he recorded Blues Bag for Vee-Jay, playing bass clarinet in a group that included Lee Morgan, Curtis Fuller and Blakey. Work was scarce, and in 1966 he became leader of the posthumous band of Glenn Miller, billed as "The World Famous Glenn Miller Orchestra, Directed by Buddy DeFranco." He led it until 1974, making a Tokyo album in 1966 and a live album at London's Royal Festival Hall in 1971; he later said he had stopped playing around 1970 and resumed his jazz career in 1975.

From the mid-1970s he combined touring and recording with teaching, giving clinics (many for Yamaha, whose clarinets he played) and publishing the woodwind study book Hand in Hand with Hanon. He hosted a public television series, The Buddy DeFranco Jazz Forum, and appeared on The Tonight Show under both Steve Allen and Johnny Carson. Starting in the early 1980s he co-led a long series of albums with the vibraphonist Terry Gibbs, beginning with Jazz Party: First Time Together (1981) and including Kings of Swing (1992) with Herb Ellis. He recorded with the guitarist Martin Taylor in Britain from 1983, made Hark with the Oscar Peterson quartet in 1985, and earned a Grammy nomination for the 1997 duo album You Must Believe in Swing with the pianist Dave McKenna. Later albums included Cookin' the Books (2003) with the John Pizzarelli trio and Charlie Cat 2 (2007). He recorded more than 160 albums, won twenty DownBeat awards, nine Metronome awards and sixteen Playboy All-Star awards, and was named an NEA Jazz Master in 2006; the University of Montana in Missoula holds a Buddy DeFranco Jazz Festival each April. He passed away in Panama City, Florida, on December 24, 2014, at the age of 91.

DeFranco was virtually alone among clarinetists in adapting the instrument to bebop's fast tempos and dense harmonies, and he stayed with the clarinet when most swing-era players had given it up. His starting points were the driving arpeggios of Benny Goodman and the harmonic fluency of Artie Shaw, whom he named as his favorite clarinetist, and from Tommy Dorsey he took the habit of shaping long, vocal phrases. Charlie Parker supplied the vocabulary and the articulation, and DeFranco insisted that a classical grounding was essential to meeting the clarinet's demands, with its several registers and open-hole fingering. The result was a fast, clean, fiery sound with precise intonation that kept a swing player's feel for time; he credited Art Blakey and the Basie band with teaching him how to relax into the beat. Scott Yanow of AllMusic calls him one of the great clarinetists and, until the rise of Eddie Daniels, the top clarinetist to emerge since 1940, adding that he never became a household name because the instrument fell from favor after the swing era. The Japanese clarinetist Eiji Kitamura studied his playing, according to Kitamura's own profile, and the two recorded together in 1982 and 2008.