A child prodigy on the piano, Szell was educated in Vienna. His conducting debut came at the age of 16 with the Vienna Symphony Orchestra. Richard Strauss appointed him to the staff of the Berlin State Opera in 1915, and he was subsequently engaged by opera houses in Prague, Darmstadt, and Düsseldorf. He was first conductor at the Berlin State Opera (1924–29), at the German Theatre in Prague (1930–37), and conductor of the Scottish Orchestra (1937–39). Before World War II he appeared with orchestras in various countries, including the United States and the Soviet Union.

After the outbreak of war in 1939, Szell immigrated to the United States, conducting in many American cities. From 1942 to 1946 he conducted at the Metropolitan Opera in New York City, and he became a naturalized U.S. citizen in 1946. That same year he took up his post as musical director of the Cleveland Orchestra, holding it until his death in 1970. Szell toured widely with that organization, winning an international reputation for the clarity, balance, and intensity of his performances of works by Wolfgang Amadeus Mozart, Ludwig van Beethoven, Franz Schubert, Johannes Brahms, and Gustav Mahler.