Hampton moved to Chicago as a child and began his career as a drummer. He relocated to Los Angeles to play drums in Les Hite's band. They soon became the house band for Frank Sebastian's New Cotton Club, a popular L.A. jazz club.
During a 1930 recording date in the NBC studios in L.A., Louis Armstrong discovered a vibraphone (which is similar to a xylophone, but with metal bars and a vibrato mechanism). He asked Hampton if he could play it. Hampton, who knew how to play the xylophone, tried it and they agreed to record a few records with Hamp on vibes. Hampton is credited with popularizing the vibraphone as a jazz instrument.
In the mid-30s, the Benny Goodman Orchestra came to Los Angeles to play the Palomar Ballroom. John Hammond brought Goodman to see Hampton play. Goodman asked Hampton to move to New York City and join Goodman, Teddy Wilson, and Gene Krupa to form the Benny Goodman Quartet. The Quartet was one of the first racially integrated bands to record and play before wide audiences.
While Hampton worked for Goodman in New York, he recorded with several different small groups known as the Lionel Hampton Orchestra. In the early 40s he left the Goodman organization to form his own touring band.
Hampton's band fostered the talents of Illinois Jacquet, Dexter Gordon, Ernie Royal, Jack McVea, Charlie Mingus, Monk Montgomery, Wes Montgomery, Quincy Jones, Benny Golson, Fats Navarro, Kenny Dorham, Clifford Brown, Dinah Washington, Betty Carter, Joe Williams, Arnett Cobb, and Earl Bostic, among many others.
His wife, Gladys Hampton, was his manager throughout much of his career. Many musicians recall that Lionel ran the music and Gladys ran the business.
Hampton's recording of "Flying Home" (1939) with the famous honking tenor sax solo by Jacquet, later refined and expanded by Cobb (1946), is considered by some to be the first rock and roll record. Quincy Jones once stated that Hamp was like a rock and roll musician in that "Hamp would go for the throat every night and the people would freak out".
He was known for his tireless energy and his skill on the vibes, drums, and lightning speed two-fingered piano. The bars on the vibraphone are laid out like the piano; Hampton played both instruments the same way.
Beginning in the mid-1980s, Hampton and his band started playing at the University of Idaho's jazz concert, which in 1985 was renamed the Lionel Hampton Jazz Festival. In 1987 the University's music college was renamed the Lionel Hampton School of Music, the first and only university music college to be named after a jazz musician.
Lionel Hampton died of cardiac arrest at Mount Sinai Medical Center in New York at about 06:15 AM, on August 31, 2002. He was interred in the Woodlawn Cemetery, Bronx, New York.