Pietro painted at Arezzo, thence moved to Florence. The date of this first Florentine sojourn is by no means settled; some make it as early as 1470, others push the date to 1479. According to Vasari, he apprenticed in the atelier of Andrea del Verrocchio alongside Leonardo da Vinci. He may have learned perspective from Piero della Francesca. In 1472 he must have completed his apprenticeship, for he was enrolled as a painter in the confraternity of St Luke.
Perugino was one of the earliest Italian practitioners of oil painting. Some of his early works were extensive frescoes for the convent of the Ingesati fathers, destroyed during the siege of Florence, 1537; he produced for them also many cartoons, which they executed with brilliant effect in stained glass. A good specimen of his early style in tempera is the tondo (circular picture) in the Musée du Louvre of the Virgin and Child Enthroned between Saints.
Perugino, aged forty, left Rome after completion of the Sistine Chapel work in 1486, and by autumn was in Florence. Here he figured by no means advantageously in a criminal court case. In July 1487 he and another Perugian painter named Aulista di Angelo were convicted, on their own confession, of having in December waylaid with staves someone (the name does not appear) in the streets near Pietro Maggiore. Perugino merely intended assault and battery, but Aulista meant to commit murder. The more illustrious culprit, guilty of the lesser offence, was fined ten gold florins, and the other was exiled for life.
Between 1486 and 1499 Perugino worked chiefly in Florence, making one journey to Rome and several to Perugia, where he may have maintained a second studio. He had an established studio in Florence, and received a great number of commissions. His Pietà (1495) in the Palazzo Pitti is an uncharacteristically stark work that avoids Perugino's sometimes too easy sentimental piety.
In 1499 the guild of the cambio (money-changers or bankers) of Perugia asked him to decorate their audience-hall. This extensive scheme, which may have been finished by 1500, comprised the painting of the vault with the seven planets and the signs of the zodiac (Perugino being responsible for the designs and his pupils most probably for the execution) and the representation on the walls of two sacred subjects: the Nativity and Transfiguration; in addition, the Eternal Father, the cardinal virtues of Justice, Prudence, Temperance and Fortitude, Cato as the emblem of wisdom, and numerous life-sized figures of classic worthies, prophets and sibyls figured in the program. On the mid-pilaster of the hall Perugino placed his own portrait in bust-form. It is probable that Raphael, who in boyhood, towards 1496, had been placed by his uncles under the tuition of Perugino, bore a hand in the work of the vaulting.
Perugino was made one of the priors of Perugia in 1501. On one occasion Michelangelo told Perugino to his face that he was a bungler in art (goffo nell arte): Vannucci brought an action for defamation of character, unsuccessfully. Put on his mettle by this mortifying transaction, he produced the masterpiece of the Madonna and Saints for the Certosa of Pavia, now disassembled and scattered among museums: the only portion in the Certosa is God the Father with cherubim. An Annunciation has disappeared; three panels, the Virgin adoring the infant Christ, St. Michael and St. Raphael with Tobias are among the treasures of the National Gallery, London. This was succeeded in 1505 by an Assumption, in the Cappella dei Rabatta, in the church of the Servi in Florence. The painting may have been executed chiefly by a pupil, and was at any rate a failure: it was much decried; Perugino lost his students; and towards 1506 he once more and finally abandoned Florence, going to Perugia, and thence in a year or two to Rome.
Pope Julius II had summoned Perugino to paint the Stanza of the Incendio del Borgo in the Vatican City; but he soon preferred a younger competitor, Raphael, who had been trained by Perugino; and Vannucci, after painting the ceiling with figures of God the Father in different glories, in five medallion-subjects, retired from Rome to Perugia from 1512. Among his latest works, many of which decline into repetitious studio routine, one of the best is the extensive altarpiece (painted between 1512 and 1517) of the church of San Agostino in Perugia, also now dispersed.
Perugino's last frescoes were painted for the church of the Madonna delle Lacrime in Trevi (1521, signed and dated), the monastery of Sant'Agnese in Perugia, and in 1522 for the church of Castello di Fortignano. Both series have disappeared from their places, the second being now in the Victoria and Albert Museum. He was still at Fontignano in 1524 when he died of the the plague. Like other plague victims, he was hastily buried in an unconsecrated field, the precise spot now unknown.
Vasari is our chief, but not sole, authority for saying Perugino had very little religion, and openly doubted the soul's immortality. It is difficult to reconcile this discrepancy, and certainly not a little difficult also to suppose that Vasari was totally mistaken in his assertion; he was born twenty years before Perugino's death, and must have talked with scores of people to whom the Umbrian painter had been well known. We have to remark that Perugino in 1494 painted his own portrait (illustration, upper right), now in the Uffizi Gallery, and into this he introduced a scroll lettered Timete Deum. That an open disbeliever should inscribe himself with Timete Deum seems odd. The portrait in question shows a plump face, with small dark eyes, a short but well-cut nose, and sensuous lips; the neck is thick, the hair bushy and frizzled, and the general air imposing. The later portrait in the Cambio of Perugia shows the same face with traces of added years. Perugino died possessed of considerable property, leaving three sons.
In 1495 he signed and dated a Deposition for the Florentine convent of Santa Chiara (Palazzo Pitti). Towards 1496 he frescoed a Crucifixion, commissioned in 1493 for Maria Maddalena de' Pazzi, Florence (the Pazzi Crucifixion). The attribution to him of the picture of the marriage of Joseph and the Virgin Mary (the Sposalizio) now in the museum of Caen, which indisputably served as the original, to a great extent, of the still more famous Sposalizio painted by Raphael in 1504 (Accademia di Brera, Milan), is now questioned, and it is assigned to Lo Spagna. A vastly finer work of Perugino's was the polyptych of the Ascension of Christ painted ca 1496–98 for the church of S. Pietro of Perugia, (Municipal Museum, Lyon); the other portions of the same altarpiece are dispersed in other galleries.
In the chapel of the Disciplinati of Città della Pieve is an Adoration of the Magi, a square of 6.5 m containing about thirty life-sized figures; this was executed, with scarcely credible celerity, from the 1st to 25th of March (or thereabouts) in 1505, and must no doubt be in great part the work of Vannucci's pupils. In 1507, when the master's work had for years been in a course of decline and his performances were generally weak, he produced. nevertheless, one of his best; pictures — the Virgin between Saint Jerome and Saint Francis, how in the Palazzo Penna. In the church of S. Onofrio in Florence is a much lauded and much debated fresco of the Last Supper, a careful and blandly correct but uninspired work; it has been ascribed to Perugino by some connoisseurs, by others to Raphael; it may more probably be by some different pupil of the Umbrian master.
Among his pupils was Giovanni di Pietro (lo Spagna).