Lionel Hampton was born in 1908 and was raised by his grandmother. Sources disagree as to whether he was born in Louisville, Kentucky, Birmingham, Alabama, or Dayton, Ohio. He spent his youth in Kenosha, Wisconsin before he and his family moved to Chicago, Illinois in 1916.

As a child Hampton was a member of the Bud Billiken Club, an alternative to the Boy Scouts of America due to segregation. During the 1920s, while still a teenager, Hampton took xylophone lessons from Jimmy Bertrand and started playing drums. Hampton was raised Roman Catholic, and started out playing fife drum at the Holy Rosary Academy near Chicago.

Hampton began his career playing drums for the Chicago Defender Newsboy's Band while still a teenager in Chicago, a group that was led by a Major N. Clark Smith. He moved to California in 1927 or 1928, playing drums for the Dixieland Blue-Blowers.

He made his recording debut with The Quality Serenaders led by Paul Howard, then left for Culver City and drummed for the Les Hite band at Sebastian's Cotton Club. During this period he began practicing on the vibraphone. In 1930 Louis Armstrong came to California and hired the Les Hite band, asking Hampton if he would play vibes on two songs. So began his career as a vibraphonist, popularizing the use of the instrument ever since.

While working with the Les Hite band, Hampton also occasionally did some performing with Nat Shilkrer and his orchestra. During the early 1930s he studied music at the University of Southern California. In 1934 he led his own orchestra, and then appeared in the 1936 Bing Crosby film Pennies From Heaven alongside Louis Armstrong (wearing a mask in a scene while playing drums).

Also in November 1936, the Benny Goodman Orchestra came to Los Angeles to play the Palomar Ballroom. John Hammond brought Goodman to see Hampton play. Hampton backed Billie Holiday with the Goodman orchestra, who was discovered by John Hammond and Goodman asked Hampton to join the Benny Goodman Trio, made up of Goodman, Teddy Wilson, and Gene Krupa, expanding it into the Benny Goodman Quartet. The Trio and Quartet were among the first racially integrated jazz groups to record and play before wide audiences, and were a leading small-group in an era when jazz was dominated by big bands.

While Hampton worked for Goodman in New York, he recorded with several different small groups known as the Lionel Hampton Orchestra as well as assorted small groups within the Goodman band. In 1940 Hampton left the Goodman organization under amicable circumstances to form his own big band.

Hampton's orchestra became very popular during the 1940s and early 1950s. His third recording with them in 1942 produced a classic version of "Flying Home", featuring a solo by Illinois Jacquet that paved the way for Rhythm & Blues. The selection became very popular, and so in 1944 Hampton recorded "Flying Home, Number Two" featuring Arnett Cobb.

The song went on to become the theme song for all three men. Guitarist Billy Mackel first joined Hampton in 1944, and would perform and record with him almost continuously through the late 1970s. In 1947 he recorded Stardust at a "Just Jazz" concert with Charlie Shavers and Slam Stewart.

Hampton's band played in a jazz, merged with rhythm & blues vein from around 1945 to the early 1950s. Represented in recordings on Decca Records, the band included performers that achieved renown in their own right in the 1950s and 1960s, composer and bassist Charles Mingus, saxophonist Johnny Griffin, guitarist Wes Montgomery, vocalist Dinah Washington and keyboardist Milt Buckner.

Other noteworthy performers in the orchestra then included trumpeters Dizzy Gillespie, Cat Anderson, Kenny Dorham and Snooky Young, trombonist Jimmy Cleveland and saxophonists Illinois Jacquet and Jerome Richardson.

In 1953 the orchestra toured Europe with Clifford Brown, Gigi Gryce, George Wallington and Art Farmer in his lineup; Quincy Jones was arranger/trumpeter and Annie Ross sang. Hampton continued to record with small groups and jam sessions during the 1940s and 1950s, with groups including Oscar Peterson, Art Tatum and Buddy DeFranco among others.

In 1955 he was in California working on The Benny Goodman Story he was able to record sessions with Stan Getz and Art Tatum as well as with his own big band.