Of Umbrian origins, the settlement became a Roman possession under the name of Asisium. Until the 13th century the extension of the town coincided with the Roman one. Bishop Rufinus evangelised the inhabitants in 238 A .D. Taken by Totila in 545, it then became part of the Longobard and Frankish Duchy of Spoleto. In the 11th century a free commune is constituted: being of Ghibelline faith it always lived in opposition to the Guelfish Perugia. In 1198, taking advantage from the absence of the imperial vicar, Conrad von Lutzen, the inhabitants of Assisi attacked his fortress.
As Perugia tried to interfere with the liberation struggle of Assisi , the latter marched against Perugia and was beaten in a battle at Ponte San Giovanni. Among the prisoners taken by Perugia was a certain 22-years-old Giovanni di Bernardone, called Francesco. He was born in the winter between 1181 and 1182 as the child of a wealthy textile tradesman, Pietro di Bernardone, whose family came from Lucca , and his Provençal wife Pica. After the captivity in Perugia , Francesco decided to make a reputation for knighthood participating in the crusade of Walter de Brienne, but an illness forced him to renounce already at Spoleto. In the meantime, in Assisi in 1197 was christened the future emperor Frederick II, three years after his birth on the market square of Jesi (near Ancona ). Francesco decided to change his life, renouncing to the riches and the eases of his family fortune and praying at San Damiano had the vision which ordered him to restore the Church (1205).
In 1208, Francesco who had in the meantime received as a gift from the Benedictines the chapel of S. Maria degli Angeli, called as well the Porziuncola, founded his order of the Grey-Friars. After his encounter with Chiara di Favarone di Offreduccio, daughter of a noble Assisi family, in 1212 he founded for her a second order, the Clarisse's. Finally, in 1221 he founded in Cannara the Third Order (a lay-order). In 1224 he recieved at La Verna the stigmata and in 1226 expired at the Porziuncola. Only two years later he was proclaimed saint and the day after Pope Gregory IX laid the foundation stone of the church and the convent planned by Brother Elias, a companion of the Saint. Also St. Clare was canonised two years after her death of 1253 and a year later begun the construction of the church in her honour.
Notwithstanding the presence of these two eminent religious figures the future history of Assisi did not show many traces of it. In 1316 it enlarged its town-walls, incorporating the convent and church of St. Francis , the Benedictine convent of S. Peter and the town quarter Borgo Aretino. The decline of Assisi begun after the black death in 1348. In order to assure the Pontifical dominion over Assisi , Cardinal Aegidius Albornoz erected in 1367 the Rocca Maggiore on top of the ruins of the former imperial fortress.
Since the 14th century and until the 16th century the two major Assisi families, the Nepis (of the upper town=Parte de Sopra) and the Fiumi (of the lower town=Parte de Sotto) continued to fight each other bitterly, although the town was dominated for long periods by several seignories (Biordo Michelotti, Broglio di Trinci, Galeazzo Visconti, Braccio Fortebraccio, Francesco Sforza, Jacopo Piccinino). Only under the reign of Pope Pius II Piccolomini (1458-64) the domination of the Church over Assisi has been definitely restored.