Studied with Piero della Francesca, was influenced by Pollaiolo and Perugino. He worked in Cortona, Florence, Loreto (Marche), città di Castello (Umbria) and Arezzo, Perugia, Volterra, Rome and Orvieto. Works by S. (frescoes in the Sistine chapel of the Vatican, 1481−83; "pan", 1488−90, died in 1945; the frescoes in the cloister of the convent of Monteoliveto Maggiore in Tuscany, 1497, and in the chapel of San Brizio the Cathedral of Orvieto, 1499−1504) is rather tough, masculine strength and heroism of new imagery. Special attention Signorelli was paid to the study of the forms and movements of human figures, passing them stressed volume in a clear and hard outline, which in the later works of Signorelli has some kind of motionlessness.
He was born and died in Cortona, in connection with what some sources call him Luca of Cortona. Pupil of Piero della Francesca, he has also experienced the influence of Antonio pollaiuolo in the transmission of human anatomy and movement. Worked in many cities of Central Italy, as in the centers of the Renaissance, in the courts of Lorenzo de ' Medici in Florence, and federigo da Montefeltro in Urbino), and provincial.
In 1481−1482 years participated in the decoration of the Sistine chapel in Rome, writing together with Bartolomeo della Gatta fresco "scenes from the life of Moses." In the Sistine chapel worked at one time with Perugino, whose influence art historians have noted in the frescoes, Signorelli performed for sacristie the sanctuary of Loreto, and in the altar of St. Onuphrius for the Cathedral of Perugia (1484).
Often in Florence, and in 1490 wrote to Lorenzo the Magnificent’s famous painting "Education of pan" (died in Berlin during the Second world war) and the Tondo of the "Madonna and child" (Uffizi).
The greatest fame brought Signorelli frescoes in the monastery of the Abbey of Monte Oliveto Maggiore (Tuscany, 1496−1498) "History of St. Benedict" and "End of the world" for the chapel of San Brizio of the Cathedral at Orvieto (1499−1502). Frescoes of the chapel of San Brizio, one of the most impressive cycles on the theme of the Apocalypse, represent the transition to the painting of the XVI century. Full here revealed the talent Signorelli is one of the most brilliant draughtsmen of the Renaissance. According to sources, Michelangelo was inspired by this work, creating your "judgment".
In 1512 he was appointed Ambassador of Cortona in Florence.
The last years of his life were spent in his native city, where he was head of the workshop.