He began his career as a film writer by adapting the lives of historical figures in films such as Pietro Micca or Don Bosco (1935 film) in the period immediately before the outbreak of World War II.
In the Post-war period, the advent of the neorealist movement brought him closer to the likes of Roberto Rossellini and Vittorio De Sica, with whom he collaborated on the screenplays of some of the major works of the period, from Rome, Open City to Sciuscià. He also worked in parallel as a producer and production manager; in 1949 he founded the film production company Colonna Film in Rome.
Nominated four times for an Academy Award, he was awarded two David di Donatello and two Nastro d'Argento. The city of Gorizia has established the Sergio Amidei Prize, an international award dedicated to him, which honors the best screenwriters on the world film scene.
He was romantically linked, for a time, to actress Maria Michi. He died on April 14, 1981, in Rome. He is buried at the Campo Verano.