Its origin, like all older universities, was a Cathedral School, whose existence can be traced back to 1130. The university was founded in 1134 and recognized as a "General School of the Kingdom" by the Leonese King Alfonso IX in 1218. Granted Royal Chart by King Alfonso X, dated 8 May 1254, as the University of Salamanca this established the rules for organization and financial endowment.
On the basis of a papal bull by Alexander IV in 1255, which confirmed the Royal Charter of Alfonso X, the school obtained the title of University.
The historical phrases Quod natura non dat, Salmantica non praestat (what nature does not give, Salamanca does not lend, in Latin) and Multos et doctissimos Salmantica habet (many and very versed Salamanca has) give an idea of the prestige the institution rapidly acquired.
In the reign of King Ferdinand II of Aragon and Queen Isabella I of Castile, the Spanish government was revamped. Contemporary with the Spanish Inquisition, the expulsion of the Jews and Muslims, and the conquest of Granada, there was a certain professionalization of the apparatus of the state. This involved the massive employment of "letrados", i.e., bureaucrats and lawyers, who were "licenciados" (university graduates), particularly, of Salamanca, and the newly founded University of Alcalá. These men staffed the various councils of state, including, eventually, the Consejo de Indias and Casa de Contratacion, the two highest bodies in metropolitan Spain for the government of the Spanish Empire in the New World.
While Columbus was lobbying the King and Queen for a contract to seek out a western route to the Indies, he made his case to a council of geographers at the University of Salamanca. In the next century, the morality of colonization in the Indies was debated by the School of Salamanca, along with questions of economics, philosophy and theology.
By the end of the Spanish Golden Age (c. 1550–1715), the quality of academics in Spanish universities declined. The frequency of the awarding of degrees dropped, the range of studies shrank, and there was a sharp decline in the number of its students. The centuries-old European wide prestige of Salamanca declined.
Like Oxford and Cambridge, Salamanca had a number of colleges (Colegios Mayores). These were founded as charitable institutions to enable poor scholars to attend the University. By the eighteenth century they had become closed corporations controlled by the families of their founders, and dominated the university between them. Most were destroyed by Napoleon's troops. Today some have been turned into faculty buildings while others survive as halls of residence.
In the 19th century, the Spanish government dissolved the university's faculties of canon law and theology. They were later reestablished in the 1940s as part of the Pontifical University of Salamanca.