At first a professional lute player, Sebastiano began his career as a painter later than most of his contemporaries. He was a pupil of Giovanni Bellini and of Giorgione, whose influence is apparent in his work. His works in fact were often confused with Giorgione's—e.g., “Salome” (1510; National Gallery, London). In 1511 Sebastiano went to Rome, where the Sienese banker Agostino Chigi had engaged him to decorate his newly built Villa Farnesina. Shortly after completing this commission, Sebastiano settled permanently in Rome, where he became a member of Raphael's (Raphael) circle of artists and soon showed himself to be a notable portraitist.

About 1515 Sebastiano came under the influence of Michelangelo and began collaborating with that artist. From drawings and cartoons by Michelangelo he executed his best-known work, the “Pietà” (c. 1517; Civic Museum, Viterbo), as well as the “Flagellation” (1516–24; Borgherini Chapel, San Pietro in Montorio, Rome) and the “Raising of Lazarus” (1519; National Gallery, London). Michelangelo's opinion of him was so high that he thought by correcting his rather dull draftsmanship, he could make Sebastiano the best painter in Rome. In his Roman work Sebastiano combined the warm colouring of the Venetian school with the anatomical clarity and firm sculptural drawing probably resulting from his association with Michelangelo.

From 1519 to 1530 Sebastiano had an unparalleled reputation in Rome as a portraitist. Among the best of his later portraits are those of “Andrea Doria” (1526; Doria Pamphili Gallery, Rome) and of “Clement VII” (1526; Capodimonte Museum, Naples). In 1531 Pope Clement VII bestowed upon Sebastiano the lucrative post of keeper of the papal seal (piombino is Italian for “lead seal,” hence his nickname). During the last 17 years of his life this economic security seems to have been a significant contributing factor in Sebastiano's limited production of pictures.