The original university was founded by Pope Martin V at the behest of Duke John (Jean) IV of Brabant, who modeled its constitution after the University of Paris. In 1517 the Dutch scholar Desiderius Erasmus (Erasmus, Desiderius) became involved with the founding of Leuven's Trilingual College, “the school of the new learning in Europe,” for the study of Greek, Latin, and Hebrew. During the 16th century Justus Lipsius (Lipsius, Justus) and Gerard Mercator (Mercator, Gerardus) were also on the faculty. At that time Leuven was the chief centre of anti-Reformation thought. The forces of the French Revolution suppressed the university in 1797, but in 1834 the Belgian episcopate reestablished it as a French-language, Roman Catholic university.

The university's famous library was burned during the German invasion in 1914, and a new library was built (1921–28) with American funds and books donated by many nations. The library was again destroyed by fire during the German invasion in 1940 but was subsequently restored.

In the 1930s the university began to teach some courses in Flemish. Although the Belgian government had previously forbidden the use of Flemish in universities, it changed its policy in 1932 in response to growing pressure from Belgium's sizable Flemish-speaking population. In 1969, after student riots, ethnic protests, and government upheavals, the Catholic University was reorganized into separate Flemish- and French-language divisions. Each of the two divisions was given separate legal status in 1970, and the first faculties were installed in Louvain-la-Neuve in 1972.