Lewis was born Melvin Sokoloff in Buffalo, New York, to Russian-Jewish immigrant parents Samuel and Mildred Sokoloff. He started playing professionally as a teen, eventually joining Stan Kenton in 1954. His musical career brought him to Los Angeles in 1957 and New York City in 1963.
In 1966 in New York, he teamed up with Thad Jones to lead the Thad Jones/Mel Lewis Orchestra. The group started as informal jam sessions with the top studio and jazz musicians of the city, but eventually began performing regularly on Monday nights at the famed venue, the Village Vanguard. In 1979, the band won a Grammy for their album Live in Munich. Like all of the musicians in the band, it was only a sideline. In 1976, he released an album titled Mel Lewis and Friends that featured him leading a smaller sextet that allowed freedom and improvisation.