Durante was born in Brooklyn, the third of four children born to Italian-Americans Mitch Durante (1855-1929) and Margaret Durante (1858-1936). A product of working-class New York, Durante dropped out of school in the eighth grade to become a full-time ragtime pianist, working the city circuit and earning the nickname "Ragtime Jimmy," before he joined one of the first recognisable jazz bands in New York, the Original New Orleans Jazz Band.

Durante was the only member of the group who did not hail from New Orleans. His routine of breaking into a song to deliver a joke, with band or orchestra chord punctuation after each line became a Durante trademark. In 1920, the group was renamed Jimmy Durante's Jazz Band.

Durante became a vaudeville star and radio attraction by the mid-1920s, with a music and comedy trio called Clayton, Jackson and Durante. Lou Clayton and Eddie Jackson, probably Durante's closest friends, often reunited with Durante professionally. By 1934, he had a major record hit, his own novelty composition Inka Dinka Doo and it became his theme song for practically the rest of his life.

A year later, Durante starred in the Billy Rose stage musical, Jumbo, in which a police officer stopped him while leading a live elephant and asked him, "What are you doing with that elephant?" Durante's reply, "What elephant?", was a regular show-stopper.

He began appearing in motion pictures at about the same time, beginning with a comedy series pairing him with silent film legend Buster Keaton and continuing with such offerings as The Wet Parade (1932), The Man Who Came to Dinner (1942, playing Banjo, a character based on Harpo Marx), Ziegfeld Follies (1946), Billy Rose's Jumbo (1962, based on the 1935 musical) and It's a Mad, Mad, Mad, Mad World (1963).

On September 10, 1933 Durante appeared on Eddie Cantor's popular The Chase and Sanborn Hour, continuing until November 12 of that year. When Cantor departed, Durante took over the NBC show as its star from April 22 to September 30, 1934, moving on to The Jumbo Fire Chief Program (1935-36).

He teamed with Garry Moore for The Durante-Moore Show in 1943. Durante's comic chemistry with the young, brushcut Moore brought Durante an even larger audience. "Dat's my boy dat said dat!" became an instant catchphrase. The duo became one of the nation's favorites for the rest of the decade, including a well-reviewed Armed Forces Radio Network command performance with Frank Sinatra that remains a favorite of radio collectors today.

Moore left in mid-1947, and the program returned October 1, 1947 as The Jimmy Durante Show. Durante worked in radio for three years after Moore's 1947 departure, including a reunion of Clayton, Jackson and Durante on his April 21, 1948 broadcast.

Durante made his television debut on November 1, 1950, though he kept a presence in radio as one of the frequent guests on Tallulah Bankhead's two-year, NBC comedy-variety show, The Big Show. Durante was one of the cast on the show's premiere November 5, 1950. The rest of the cast included humorist Fred Allen, singers Mindy Carson and Frankie Laine, stage musical performer Ethel Merman, actors Jose Ferrer and Paul Lukas, and comic-singer Danny Thomas (about to become a major television star in his own right).

A highlight of the show was Durante and Thomas, whose own nose rivaled Durante's, in a routine in which Durante accused Thomas of stealing his nose. "Stay outta dis, No-Nose!" Durante barked at Bankhead to a big laugh.

Beginning in the early 1950s, Durante teamed with sidekick Sonny King, a collaboration that would continue until Durante's death. Jimmy could be seen regularly in Las Vegas after Sunday mass outside of the Guardian Angel Cathedral standing next to the priest and greeting the people as they left mass.

On August 4, 1955, The Jimmy Durante Show was the venue of the last performance by the famous Brazilian singer Carmen Miranda. Miranda fell to her knees while dancing with Durante, who instinctively told the band to "stop da music!".

He helped Miranda up to her feet as she laughed "I'm all out of breath!". "Dat's OK, honey, I'll take yer lines" Durante replied. Miranda laughed again and quickly pulled herself together, finishing the show. However, the next morning, August 5, Carmen died at home from heart failure.