His name derives from that of his master, Cosimo Rosselli, whom he assisted (1481) in the frescoes “Crossing of the Red Sea” and “Sermon on the Mount” in the Sistine Chapel in the Vatican. There he saw the frescoes of Sandro Botticelli and Domenico Ghirlandaio, whose styles dominate his early “Story of Jason” (1486; National Gallery of South Africa, Cape Town). In “The Visitation with Two Saints” (c. 1487; National Gallery of Art, Washington, D.C.), the permanent influence of the enamel-like colours of Hugo van der Goes' “Portinari Altarpiece” is first visible.

Piero's mature style is exemplified by his mythological paintings, which exhibit a bizarre, romantic fantasy. Many are based on Vitruvius' account of the evolution of man. They are filled with fantastic hybrid forms of men and animals engaged in revels (“The Discovery of Wine,” c. 1500; Fogg Art Museum, Cambridge, Mass.) or in fighting (“Battle of the Centaurs and the Lapiths,” 1486; National Gallery, London). Others show early man learning to use fire (“A Forest Fire,” c. 1487; Ashmolean Museum, Oxford) and tools (“Vulcan and Aeolus,” c. 1486; National Gallery of Canada, Ottawa). The multitude of firm, glossy-skinned nudes in these paintings show Piero's interest in Luca Signorelli's work. But, while “The Discovery of Honey” (c. 1500; Worcester Art Museum, Worcester, Mass.) retains Signorelli's figure types, its forms are more softly modeled, and its light is warmer, showing Piero's mastery of the new technique of oil painting. In the “Rescue of Andromeda” (c. 1515; Uffizi, Florence), Piero adopts Leonardo da Vinci's sfumato (smoky light and shade) to achieve a new lush, atmospheric effect.

Piero painted several portraits, of which the best known is the memorial bust of Simonetta Vespucci (c. 1498; Condé Museum, Chantilly, France), mistress of Giuliano de' Medici. Simonetta is partly nude, and her rhythmic profile is accentuated by the black cloud placed behind it. She wears a gold necklace, around which two snakes coil, possibly an allusion to her death from consumption. The transience of youth and beauty is the theme of the famous “Death of Procris” (c. 1490–1500; National Gallery, London). The softly undulating form of the accidentally slain Procris lies in a meadow bathed in a golden light while a curious satyr kneels beside her and her faithful dog—considered the first humanized dog in art—mourns at her feet.

Piero's art reflects his bizarre, misanthropic personality. He belonged to no school of painting and operated outside the official artistic milieu. Instead, he borrowed from many artists, incorporating elements of their style into his own idiosyncratic manner. He painted many works to please only himself (an unusual practice for the time) and declared that he often found inspiration for his paintings in the stains on walls.