Originally from Los Angeles, California, Lewis attended The University of Southern California and at age 16, joined the Los Angeles Philharmonic, becoming the first black instrumentalist in a major symphony orchestra. After six years as a double-bassist with the Los Angeles Philharmonic Orchestra, he played double-bass with and conducted the Seventh Army Symphony in Germany and the Netherlands while serving in the United States Armed Forces (1955–1956).
After returning to the USA, Lewis founded the Los Angeles Chamber Orchestra. In 1963 he travelled with his orchestra in Europe under the auspices of the State Department. He gained national recognition in 1961 when he was appointed assistant conductor of the Los Angeles Philharmonic Orchestra under Zubin Mehta, a post he held from 1961-1965. In 1968 he became the conductor and musical director of the New Jersey Symphony, transforming the group from a small community ensemble into a nationally recognized orchestra. He was the first African-American to lead a major symphony orchestra. He made his Metropolitan Opera debut in 1972 and after retiring from the New Jersey Symphony in 1976, he toured as a guest conductor in all of the major opera houses. From 1989 to 1991, when Kees Bakels succeeded him, he was principal conductor of the Netherlands Radio Symphony.
From 1960 to 1979, Lewis was married to famed opera singer Marilyn Horne, who often credits him with her early development as a singer. They lived together in Echo Park, California, and had a daughter, Angela.