He started as the apprentice of Francesco Squarcione in Padua. In 1453 Mantegna married Jacopo Bellini's daughter. In 1460, Mantegna was appointed court artist to the Gonzaga family, rulers of Mantua.
His work is characterized by classical elements (such as an attempt to mimic a Roman bas-relief in paint), and shows a strong influence by Donatello. His influence can be seen in the work of his brother-in-law Giovanni Bellini and Albrecht Dürer.
His work includes frescoes in the Ovetari Chapel in Padua (1448-59), the San Zeno Altarpiece (1456-59) Judith with the Head of Holofernes, The Agony in the Garden (c.1465), and the frescoed ceiling of the Camera degli Sposi at the Gonzaga family palace in Mantua.