Born in Catania, Sicily to a Maltese father and a Sicilian mother,[1] Musco worked at a number of menial, odd jobs in his youth, spending time as a barber, a shoemaker, and a mason.

In 1902 Musco began a collaboration with Nino Martoglio, who had seen him in Rome in Malia of Luigi Capuana and I Mafiusi of Giuseppe Rizzotto and Gaetano Mosca.

Martoglio became director of Musco's company in 1907, and wrote for him the plays San Giovanni decollatu and L'aria del continente.

Musco also collaborated with Pier Maria Rosso di San Secondo, author of the play Madre, and he worked with Marinella Bragaglia and Rosina Anselmi.

He was the subject of a documentary directed by Giorgio Walter Chili in 1953, C'era una volta Angelo Musco.