One of the "free" universities of Italy, it was elevated into a studium generale on September 8, 1308, by the Bull "Super specula" of Clement V. A school of arts existed by about 1200, in which medicine and law were soon taught, with a strong commitment expressed by official documents of the City Council of Perugia.

By Bull on August 1, 1318, John XXII granted the privilege of conferring degrees in civil and canon law, and on February 18, 1321, in medicine and arts.

On May 19, 1355, the Emperor Charles IV issued a Bull confirming the papal elevation and raising it to the rank of an imperial university.

The Collegio di S. Girolamo was founded by Benedetto Guidalotti, Bishop of Recanatias a free hostel for impecunious strangers who wished to study law and medicine in 1426, with Martin V's approval, and transferred (as the Sapienza nuova) to the University.

With the unification of Italy in 1860 the University of Perugia was established under the jurisdiction of the Rector and the Town Council, who issued statutes subject to approval by the Government.