In 1491, his mother Màgia died; his father died on August 1, 1494, having already remarried. Thus orphaned at eleven, Raphael was entrusted to his uncle Bartolomeo, a priest. He had already shown talent, according to Giorgio Vasari - he tells that since childhood Raphael had been "a great help to his father". His father's workshop continued and probably together with his stepmother, Raphael evidently played a part in managing it from a very early age. He is described as a "master" in 1501. In Urbino he came into contact with the works of Uccello and Signorelli. According to Vasari, his father placed him in Perugino's workshop as an apprentice "despite the tears of his mother"; the subsequent influence of Perugino on Raphael's early work is most obvious. The evidence of an apprenticeship comes only from Vasari, and has been disputed. But most modern historians agree that Raphael worked as an assistant to Perugino from around 1500.

His first documented work was an altarpiece for the church of San Nicola of Tolentino in Città di Castello, a town halfway between Perugia and Urbino. It was ordered in 1500 and finished in 1501 (it was later seriously damaged during an earthquake in 1789 and today only fragments of it remain). In the following years he painted works for other churches there (like the Wedding of the Virgin, today in the Brera) and for Perugia.