Skalkottas began violin studies at the age of five, continuing them later at the Athens conservatory and in Berlin, where he also studied composition. Influenced by Schoenberg, with whom he studied (1927–31), he began using the 12-tone method in his compositions but adhered to traditional forms. Returning to Athens in 1933, Skalkottas worked as an orchestral violinist but continued to compose.
Little of his music was performed during his lifetime, and almost none of it was published. His major works include symphonic suites, three piano concerti, four string quartets, and the overture The Return of Ulysses. His settings of Greek dances are based on Balkan folk music.