Castellitto attended the academy of dramatic art, and soon became an actor working with some small films. He is known, in Italy, for his part in "The Great Pumpkin" and "The Star Maker." His rise to fame came with the films "La famiglia", "L'ultimo bacio]", "Caterina in the Big City", "My Mother's Smile", "Mostly Martha", and especially with "Don't Move", written by his wife Margaret Mazzantini. The first film that he directed is "Libero burro" and the latest "Don't Move".
He also played Enzo Ferrari in the 2003 movie Ferrari, in which Skandar Keynes played the 8-year-old version of Enzo Ferrari.
Castellito is married and has four children.