It is likely that Signorelli was a pupil of Piero della Francesca in the 1460s. The first certain surviving work by him, a fragmentary fresco (1474) now in the museum at Città di Castello, shows a strong influence from Piero. His first signed work was a processional banner with a Madonna on one side and a Flagellation on the other; these hang in the Brera, Milan, as separate pictures. They still show links with the style of Piero, but the dominant influence is that of Florence and especially the scientific naturalism of the Pollaiuolo brothers, which suggests that Signorelli visited Florence in the 1470s. In 1479 he was elected to the Council of 18 in his native Cortona, and for the rest of his life he was active in politics.

About 1483 he went to Rome, where the “Testament of Moses” fresco in the Sistine Chapel is unanimously attributed to him. By that date his style had become fixed, his interest in dramatic action and the expression of great muscular effort marking him as an essentially Florentine naturalist. The S. Onofrio altarpiece (1484) for Perugia cathedral shows the same qualities. Between 1497 and 1498 he was at work on a fresco cycle of scenes from the life of St. Benedict in the monastery at Monteoliveto Maggiore, near Siena.

His masterpiece, the frescoes of “The End of the World” and the “Last Judgment” (1499–1502), is in the chapel of S. Brizio in Orvieto cathedral. Those frescoes, which greatly influenced Michelangelo, are crowded with powerful nudes painted in many postures that accentuate their musculature. Signorelli had little sense of colour, but here his greenish and purple devils add to the horror induced by the strained poses and the anatomical details in the decayed bodies.

When commissions in Rome and Florence became infrequent, Signorelli returned to his less sophisticated Umbrian clientele. Most of his later works betray the hands of his numerous assistants.