Born in Naples, he was a devout monk and learned casuist, trained at Avignon. On March 21, 1364, he was consecrated Archbishop of Acerenza in the Kingdom of Naples. He became Archbishop of Bari in 1377, and, on the death of Pope Gregory XI (1370–78), the Roman populace clamorously demanding a Roman pope, and the cardinals being under some haste and pressure, Prignano was unanimously chosen (April 8, 1378) as acceptable as well to the disunited French cardinals, taking the name Urban VI. He was the last Pope to be elected from outside the College of Cardinals. Immediately following the conclave most of the cardinals fled Rome before the mob could learn that not a Roman, but a subject of Joan I of Naples, had been chosen.
Prignano had developed a reputation for simplicity and frugality, even austerity, a head for business when acting Vice-Chancellor and a penchant for learning, and, according to Cristoforo di Piacenza, he was without famiglia in an age of nepotism. His great faults undid his virtues: Ludwig Pastor summed up his character: "He lacked Christian gentleness and charity. He was naturally arbitrary and extremely violent and imprudent, and when he came to deal with the burning ecclesiastical question of the day, that of reform, the consequences were disastrous.
Though the coronation was carried out in scrupulous detail, leaving no doubt as to the legitimacy of the new pontiff, the French were not particularly happy with this move and began immediately to conspire against this pope from the Regno. Urban VI did himself no favors; whereas the cardinals had expected him pliant, he was considered arrogant and angry by many of his contemporaries. Dietrich of Nieheim considered that the cardinals concluded that his elevation had turned his head, and Froissart, Leonardo Aretino, Tommaso de Acerno and St. Antoninus of Florence recorded similar conclusions.
Immediately following his election, Urban began preaching intemperately to the cardinals, insisting that the business of the curia should be carried on without gratuities and gifts, forbidding the cardinals to accept annuities from rulers and other lay persons, condemning the luxury of their lives and retinues, and the multiplication of benefices and bishoprics in their hands. Nor would he remove again to Avignon, thus alienating Charles V of France, and, according to Urban's assessment, opening the Western Schism.
The cardinals were mortally offended. Five months after his election, the French cardinals met at Anagni, inviting Urban, who realized that he would be seized and perhaps slain; in his absence they issued a manifesto of grievances (August 9), declaring the election invalid and claiming that they had been cowed by the mob into electing an Italian, followed by letters (August 20) to the missing Italian cardinals, declaring sede vacante. Then at Fondi, secretly supported by the king of France, they proceeded to elect Robert of Geneva (September 20). He took the title of Clement VII (1378–94). Thus began the Western Schism (1378–1417) which divided Catholic Christendom for nearly forty years.
Urban was excommunicated by the French pope and designated the Antichrist, while Catherine of Siena called the cardinals "devils in human form". Coluccio Salutati identified the political nature of the withdrawal: "Who does not see," the Chancellor openly addressed the French cardinals, "that you seek not the true pope, but opt solely for a Gallic pontiff. Opening rounds of argument were embodied in John of Legnano's defense of the election, De fletu ecclesiæ, written and incrementally revised between 1378 and 1380, which Urban saw to it was distributed in multiple copies, and in the numerous rebuttals that soon appeared. Events overtook the rhetoric, however; twenty-six new cardinals were created in a single day, and by an arbitrary alienation of the estates and property of the church, funds were raised for open war. At the end of May 1379 Clement went to Avignon, where he was more than ever at the mercy of the king of France. Louis, duc d'Anjou, was granted a phantom kingdom of Adria to be carved out of papal Emilia and Romagna, if he could unseat the pope at Rome.
Urban's erstwhile patroness, Joanna of Naples, deserted him in the late summer of 1378, in part because her former archbishop had become her feudal suzerain, and Urban now lost sight of the larger issues and began to commit a series of errors. He turned upon his powerful neighbor, excommunicated her as an obstinate partisan of Clement, and permitted a crusade to be preached against her. Soon her enemy and cousin, the "crafty and ambitious Charles of Durazzo, representing the Sicilian Angevin line, forgetting his French blood, was glad to be invested in the sovereignty of Naples (June 1, 1381), declared to be forfeited by Joanna— whom he murdered in 1382— and was crowned by Urban. "In return for these favours, Charles had to promise to hand over Capua, Caserta, Aversa, Nocera, Amalfi to the pope's nephew, a thoroughly worthless and immoral man. Once ensconced at Naples, Charles found his new kingdom invaded by Louis d'Anjou; hard-pressed, he reneged on his promises. In Rome the Castel Sant'Angelo was besieged and taken, and Urban forced to flee; Urban in the fall of 1383 unwisely determined to go to Naples and press Charles in person. There he found himself virtually a prisoner. After a first reconciliation, with the death of Anjou (September 20, 1384), Charles found himself freer to resist Urban's feudal pretensions, and relations took a turn for the worse; Urban was shut up in Nocera, from the walls of which he daily fulminated his anathemas against his besiegers, with bell, book and candle; a price was set on his head.
He succeeded in making his escape to Genoa. Several among his peregrine cardinals, who had been shut up in Nocera with him, determined to make a stand: they determined that a pope, who by his incapacity or blind obstinacy, might be put in the charge of one of the cardinals. Urban had them seized, tortured and put to death, "a crime unheard of through the centuries" the chronicler Egidio da Viterbo remarked.
His support had dwindled to the northern Italian states, Portugal, England, and Charles IV, Holy Roman Emperor, who brought with him the support of most of the princes and abbots of Germany.
On the death of Charles (February 24, 1386), set himself at the head of his troops, apparently with the intention of seizing Naples for his nephew if not for himself, for he had never lost sight of his feudal rights in the Regno. To raise funds he proclaimed a Jubilee, though only thirty-three years had elapsed since that celebrated under Pope Clement VI (1342–52), but before the celebration he died "unlamented at Rome of injuries caused by a fall from his mule, not without rumors of poisoning.
His successor was Pope Boniface IX (1389–1404).