Most famous for his 1956 jazz trumpet hit "Bad Penny Blues," Lyttelton is also remembered for his work on the BBC Radio series I'm Sorry I Haven't a Clue. In the late 1950s, he formed the popular Humphrey Lyttelton Band.
During the late 1940s, while studying at the Camberwell School of Art, he became acquainted with jazz clarinetist Wally Fawkes. Several years later, he recorded with American jazz musician Sidney Bechet.
From 1949 until 1956, he worked as a cartoonist for the Daily Mail.
His marriage to Pat Braithwaite resulted in a daughter named Henrietta. With his second wife, Jill Richardson, he had children named Georgina and Stephen.
He was influenced by the work of American jazz trumpeter Louis Armstrong.