Krupa was born in Chicago, Illinois. He began playing professionally in the mid 1920s with bands in Wisconsin.
Krupa moved to New York City in 1929 and worked with the band of Red Nichols. In 1934 he joined Benny Goodman's band, where his featured drum work made him a national celebrity. In 1938 he left Goodman to lead his own band, which he did until 1943. After some months back with Goodman and then with Tommy Dorsey he started a new big band-- one of the largest dance bands of the era, sometimes containing up to 40 musicians. He gradually cut down the size of the band in the late 1940s, and from 1951 on led a trio or quartet. He appeared regularly with the Jazz At the Philharmonic shows.
Krupa largely went into retirement in the late 1960s, although occasionally played in public until shortly before his death by leukemia. Gene Krupa died in Yonkers, New York.