The deeds of Gómez de Marzoa, from 1495, and those he signed with Diego de Muros II and Diego de Muros III, in 1501, to create a Grammar Studium mark the founding moment of the University of Santiago de Compostela. The creation of the Colegio Alfero, on the initiative of Alonso III de Fonseca, contributed to consolidating university studies in Compostela, which received the endorsement of Pope Julius II, in 1504, and Pope Clement VII, in 1526. In 1555, the university studies of Compostela were recognised as a Royal University.

The University of Santiago was recognised as having the rights of the major universities of Castile and, after the visit of the regent of the Audience in Galicia, Pedro de Portocarrero, academic reforms were promoted to expand studies and create new chairs. In the last quarter of the 16th century, the presence of the Society of Jesus was consolidated, which began to build a school in Compostela in 1587. The schools of San Clemente de Pasantes, in 1602, and San Xerome, in 1650, were founded.

Throughout the 18th century, the University of Compostela underwent numerous changes in its academic organisation. The changes were especially intense during the reign of Charles III, after the expulsion of the Society of Jesus in 1767 and the approval of the 1772 curriculum. In 1776, the University of Santiago began the construction of what would be its central headquarters and for the first time, in the last two decades of the 18th century, it exceeded a thousand students, most of them studying Theology, Laws and Canonic Studies, and a few studying Medicine and Surgery.

The War of Independence would empty the classrooms and the threat of suppression would hover over the University of Compostela in 1810 because of its "pro-Frenchness" and, in 1815, because of the desire of absolutists to stop the progression of liberal ideals in its classrooms. In 1824, the Calomarde Plan was approved, with marked absolutist traces. The Pidal Plan (1845) and Moyano Law (1857) certify the centralism and interventionism of the State, diminishing the autonomy of the University. The University of Santiago registered a big drop in its enrolment. At the end of the 19th century, its classrooms received fewer students than a century earlier.

In the first third of the 20th century the University experienced a wave of modernisation and democratization. In 1910, the limitations that prevented women's access were eliminated. However, the presence of women in the university classrooms of Compostela was minimum until the last quarter of the century. Some formulas of university autonomy without continuity were tested and, with the 2nd Republic, the democratization of the institution was promoted, with the participation of the students. The cartography of the University of Santiago changes with the Student Residence project. The coup d'état of 1936 opened a period of involution. From the end of the 1960s, the University became a centre of democratic resistance against Francoism.

The General Education Law (1970) promoted the expansion of university studies. University Colleges were created in Lugo, A Coruña and Vigo and University Colleges and Technical Colleges began to operate in Galician cities. The extension and decentralization of universities was combined, after the approval of the LRU in 1983, with an intense democratization of the University of Santiago and the expansion of its offer of degrees. The transfer of higher education competences to the Xunta de Galicia took place in 1987; the USC exceeded 45,000 students distributed in 7 university campuses.

The approval of the Law of Organisation of the Galician University System (1989) marked the beginning of the creation of the University of Vigo and the University of A Coruña and the redesign of the USC, located on the campuses of Compostela and Lugo. After the celebration of the 5th Centenary of USC in 1995, this consolidated a wide catalogue of degrees and the improvement of teaching quality, specialisation of the campuses, the creation of unique research centres and the design of active R+D+I policies. The construction of the European Higher Education Area brought new challenges, stimulating the internationalisation of USC and advanced its democratisation by multiplying its commitment to equality and sustainable development.