His focus was on religious subjects, rather than the increasing popular classical subject matter. His work shows the influence of his brother-in-law Andrea Mantegna. He is considered to have revolutionized Venetian painting, moving it towards a more "sensuous and colouristic style". When he died, he was chief painter to the state of Venice.
His work includes the Altarpiece with St Vincent Ferrar (1464), decoration of the Scuola Grande di San Marco (1470s) in conjunction with his brother Gentile, the portrait of Doge Leonardo Loredan (c.1501), S. Zaccaria Altarpiece (1505) and The Feast of the Gods (c.1514) painted for the study of Alfonso d'Este.