Successor to the meteoric Celestine V was an energic Roman of the Caetani family, Boniface VIII. Entangled in a local feud against the traditional rivals of his family, the Colonna, at the same time he struggled to reassure the universal supremacy of the Holy See. In 1300 he launched the first Jubilee and founded the first University of Rome. The Jubilee was an important move for Rome, as it increased further its international prestige increased and, most of all, the city's economy was boosted by the flow of pilgrims. Boniface died in 1303 after the humiliation of the Schiaffo di Anagni ("Slap of Anagni"), which signed instead the rule of the King of France over the Papacy and marked another period of decline for Rome.

Boniface's successor, Clement V, never entered in the city, starting the so-called "Babylonian Captivity", the absence of the Pope from their Roman seat in favour of Avignon, which will last for more than 70 years. This situation brought the independence of the local powers, but these revealed largely unstable; and the lack of the holy revenues caused a deep decay of Rome. For more than a century Rome had no new major buildings. Furthermore, many of the monuments of the city, including the main churches, began to ruin.