The High Renaissance style of the new century had little influence on him, and he retained the straightforward realism of his figures, which combines with an often whimsical treatment of his subjects to create the distinctive mood of his works.

In the first phase of his career, Piero was influenced by the Netherlandish naturalism of Hugo van der Goes, whose Portinari Triptych (now at the Uffizi Gallery in Florence) helped to lead the whole of Florentine painting into new channels.

He proved himself a true child of the Renaissance by depicting subjects of Classical mythology in such pictures as Venus, Mars, and Cupid, The Death of Procris, the Perseus and Andromeda series, at the Uffizi, and many others.

If, as Vasari asserts, he spent the last years of his life in gloomy retirement, the change was probably due to preacher Girolamo Savonarola, under whose influence he turned his attention once more to religious art.

Piero di Cosimo exercised considerable influence upon his fellow pupils Albertinelli and Bartolomeo della Porta, and was the master of Andrea del Sarto.