The University of Oviedo was established under the terms and conditions of the will of Archbishop Fernando de Valdés Salas (1483–1568), who was the General Inquisitor under Philip II of Spain, and funded by his estate.

In 1574 Pope Gregory XIII granted the papal bull to create the university and in 1604 Philip III issued its charter.

After the French invasion of Spain the Historical Building of the university was occupied by invading troops and lectures were suspended until the War ended in 1812.

During the 19th century, a group of liberal professors tried to bring the university closer to the working class with the Extensión Universitaria (a popular education programme sponsored by the institution).

However, this goal was not fully achieved, and on October 13, 1934, during the leftist miners revolt in Asturias, the university (including its Library and the Art Gallery) was set fire either by the revolutionaries or the government bomber airplanes.