In 1910, the Gershwin had acquired a piano for Ira's music lessons, but George took over, successfully playing by ear. He tried out various piano teachers for two years, then was introduced to Charles Hambitzer, who acted as George's mentor until Hambitzer's death in 1918. Hambitzer taught George conventional piano technique, introduced him to the music of the European masters, and encouraged him to attend orchestral concerts. (At home following such concerts, young George would attempt to reproduce at the keyboard the music he had heard). He later studied with classical composer Rubin Gold mark. His 1916 novelty rag 'Rialto Ripples' was a commercial success, and in 1918 he scored his first big national hit with his song 'Swanee'.

In 1924, George and Ira collaborated on a musical comedy, Lady Be Good. It included standards as 'Fascinating Rhythm' and 'The Man I Love. ' This was followed by Oh, Kay! (1926); Funny Face in (1927); Strike Up the Band (1927 & 1930); Girl Crazy (1930), which introduced the standard 'I Got Rhythm'; and Of Thee I Sing (1931), the first musical comedy to win a Pulitzer Prize.

It was in Hollywood, while working on the score of The Goldwyn Follies, that George Gershwin collapsed and, on July 11, 1937, died of a brain tumour. He was interred in the Westchester Hills Cemetery, Hastings-on-Hudson, New York. Gershwin had a ten-year affair with composer Kay Swift. Swift was a frequent consult of Gershwin; he named the musical Oh, Kay after her.

Posthumously, Swift arranged some of his music, transcribed some of his recordings, and collaborated with Ira on several projects. Gershwin died intestate and all his property passed to his father. The Gershwin estate continues to bring in significant royalties from licensing the copyrights on Gershwin's work. The estate supported the Sonny Bono Copyright Term Extension Act because its 1923 cutoff date was shortly before Gershwin had begun to create his most popular works. The copyrights on those works expire in 2007 in the European Union and between 2019 and 2027 in the United States of America.