Eugene Bertram Krupa was born in Chicago on January 15, 1909, the youngest of nine children of a Polish immigrant father and a mother of Polish descent born in Shamokin, Pennsylvania. His Roman Catholic parents steered him toward the priesthood. After his father's death he worked from age eleven as an errand boy for a music company and chose a drum set because it was the cheapest instrument in the wholesale catalog. He graduated from James H. Bowen High School on Chicago's southeast side and spent a year at Saint Joseph's College before deciding the priesthood was not his calling. He studied with Sanford A. Moeller and Roy Knapp, learned from the Chicago drummers Baby Dodds and Zutty Singleton, and began playing professionally in the mid-1920s with bands in Wisconsin. In 1927 the booking agency MCA placed him with Thelma Terry and Her Playboys, a Chicago house band at the Golden Pumpkin nightclub that toured the eastern and central United States; he recorded six sides with the group in 1928.

Krupa's first recordings came in December 1927, when he played on four sides ("Sugar," "China Boy," "Nobody's Sweetheart," and "Liza") by McKenzie and Condon's Chicagoans, a band sponsored by the singer and comb player Red McKenzie and led by the banjoist Eddie Condon. Its front line came out of the circle around the Austin High School Gang: cornetist Jimmy McPartland, clarinetist Frank Teschemacher, and tenor saxophonist Bud Freeman, with pianist Joe Sullivan and bassist Jim Lanigan. The date is counted among the founding documents of Chicago-style jazz, and Krupa's bass drum on it is often cited as one of the first used on a jazz record; Britannica calls him the first drummer to record with a full kit. Through the early 1930s he worked with several bands, including Red Nichols's, played in the pit orchestras for two George Gershwin musicals on Broadway, and took part in McKenzie's November 14, 1929, session with Coleman Hawkins and in a 1934 all-star studio date with Mildred Bailey. By 1934 he was the most sought-after drummer in the business, and the producer John Hammond persuaded him to join Benny Goodman's new band.

Krupa joined Goodman in December 1934. When the band's first stock arrangements fell flat at the Palomar Ballroom in Los Angeles on August 21, 1935, Krupa urged Goodman to switch to the hotter charts by Fletcher Henderson and Spud Murphy, and the crowd's response is often taken as the start of the swing era. Goodman and Krupa also played in a trio with Teddy Wilson, which became the Benny Goodman Quartet when Lionel Hampton joined in 1936. On July 6, 1937, the full band recorded Jimmy Mundy's arrangement of Louis Prima's "Sing, Sing, Sing" in Hollywood; at 8 minutes 43 seconds across both sides of a 12-inch disc, it made Krupa's tom-tom drive the center of a hit record and gave listeners one of the first extended drum solos on a commercial release. The singer Helen Ward remembered that it grew on the bandstand one night when Krupa simply would not stop drumming at the end of the third chorus. Krupa was a fixture of the Goodman band's January 16, 1938, concert at Carnegie Hall, and then, less than two months later, left after clashes with Goodman, who thought his showmanship overshadowed the music.

He formed his own orchestra in 1938, at first in the Goodman mold. In 1941 it changed character. "Drum Boogie," which Krupa wrote with the trumpeter Roy Eldridge, was first recorded on January 17, 1941, in Chicago and was filmed in extended form for Ball of Fire that year, with Martha Tilton singing for Barbara Stanwyck. Eldridge joined in April 1941, one of the first Black musicians to become a permanent member of a white big band, and the singer Anita O'Day replaced Irene Daye that spring. Together they made "Let Me Off Uptown," a top-ten hit in 1941, as well as "Georgia on My Mind," "Just a Little Bit South of North Carolina," and Eldridge's showcase on "Rockin' Chair," arranged by Benny Carter. Krupa's loyalty to Eldridge made news: a Black newspaper reported in January 1942 that he had been fined after a fistfight with a Pennsylvania restaurant manager who would not seat Eldridge with the band. In 1943 Krupa was arrested on a marijuana charge that Wikipedia and other accounts describe as falsified, and he served a jail term of about three months; the orchestra broke up. He rejoined Goodman for a few months, declined Goodman's West Coast tour, and played for several months with Tommy Dorsey's band before re-forming his own in 1944.

The new band added strings and a modern vocabulary, and under arrangers George Williams and Gerry Mulligan, who joined as staff arranger in January 1946, it scored with "Leave Us Leap," "Disc Jockey Jump," and "Lemon Drop." O'Day returned in 1945 for "Chickery Chick" and "Boogie Blues." As the big-band era faded Krupa cut the group to ten pieces in 1951 and from 1952 led trios and quartets, often with the tenor saxophonist Charlie Ventura and later Eddie Shu. He toured regularly with Norman Granz's Jazz at the Philharmonic, where the staged drum battles with Buddy Rich became a signature event; the pair's September 1952 duel at Carnegie Hall was issued by Verve as The Drum Battle, and they made two studio albums together, Krupa and Rich (recorded November 1, 1955) and Burnin' Beat (January 1962). In 1954 he and Cozy Cole started a drum school whose students included Peter Criss and Jerry Nolan, and he played often at the Metropole near Times Square in Manhattan. He appeared on screen in The Glenn Miller Story and The Benny Goodman Story, and Sal Mineo played him in the 1959 biopic The Gene Krupa Story, for which Krupa recorded the drumming and Anita O'Day made a cameo appearance.

Ill health curtailed his work in the 1960s and early 1970s, though he made Together Again! (1963) with the original Benny Goodman Quartet and led a quartet with Charlie Ventura for Verve in 1964. On April 17, 1973, his quartet of Eddie Shu, John Bunch, and Nabil Totah recorded a live set at the New School in New York. Krupa passed away in Yonkers, New York, on October 16, 1973, at age 64, of heart failure; he also had leukemia and emphysema. He is buried at Holy Cross Cemetery in Calumet City, Illinois. In 1978 he became the first drummer inducted into the Modern Drummer Hall of Fame, and the 1937 Goodman recording of "Sing, Sing, Sing" entered the Grammy Hall of Fame in 1982.

Krupa made the drummer a front-line figure. Before him the drums were largely an accompanist's tool; his tom-tom features, extended solos, and flamboyant stage manner gave the instrument a public face, and Modern Drummer magazine calls him the founding father of modern drumset playing. His own models included Baby Dodds, Zutty Singleton, Tubby Hall, Dave Tough, George Wettling, Ray Bauduc, and Chick Webb, and his early playing used press rolls before his Goodman-era work settled on driving tom-tom figures. In partnership with the Slingerland drum company, for which he was the first endorser, he pushed for tom-toms with tunable top and bottom heads, and his work with the Zildjian company helped shape the modern hi-hat and the standard names and uses of the ride, crash, and splash cymbals. The New York Times called him a revolutionary on his death. Buddy Rich, who named him as one of his biggest influences, said that before Krupa the drums were just a part of the band, and later rock drummers including John Bonham, Keith Moon, Ian Paice, and Carl Palmer have credited his example. Drummers profiled on JazzProfiles.com who name him as an early model include Jeff Hamilton, who was drawn to the drums by a Krupa record at age five, Chuck Redd, who heard Krupa and Rich as a boy, Steve Gadd, whose uncle's Krupa and Louie Bellson records led him on to Philly Joe Jones, Tito Puente, and the Japanese drummers George Kawaguchi and Takeshi Inomata, the latter of whom recorded a Krupa-style big band album, Drummer Man, in 1975.