From 1490 to 1497 he was apprenticed to G.M. Spanzotti, a minor Piedmontese artist, but he was afterward much influenced by Leonardo da Vinci and later by Raphael, who was particularly decisive in determining his mature style. He was invited to Siena in 1501 and subsequently spent the bulk of his working life there.

In 1508 he was invited to Rome by the celebrated Sienese banker Agostino Chigi and was employed by Pope Julius II in the Stanza della Segnatura in the Vatican. Although he was superseded by Raphael in 1509, some of his ceiling decoration remains. One of his most successful frescoes, the “Marriage of Alexander and Roxane” (c. 1511–12) in the Villa Farnesina, Rome, is often considered a rival as a decorative achievement to the frescoes by the school of Raphael in the same villa.

Sodoma had a peculiar gift for suggesting the sensuous beauty of the human form and an exaggerated, almost mystical, emotionalism that anticipates one aspect of the Baroque.

Sodoma gained a wide reputation during his lifetime as a homosexual; and the historian Giorgio Vasari, who disliked him, makes the most of the sobriquet Il Sodoma (the Sodomite) by which he was known from 1512 onward. It has been claimed that the nickname is likely to have been the result of a joke, but it was adopted by the artist himself and is the name by which he is now generally known.