The University of Lucerne traces its roots back to a theological school from the confessional era. It thus has the same historical background as the universities of Geneva, Lausanne, Berne and Zurich.

It was only in the 20th century, however, that the process of expansion and reorganisation began in Central Switzerland: in 1938, the school of higher education became a theological faculty, which received academic degree granting status in 1970. However, an initiative to expand the university to five faculties failed in a referendum in 1978.

It was not until two decades later that another attempt was made: the Faculty of Humanities was created in 1993, and in 2000, the citizens of Lucerne overwhelmingly approved the University Act, thus formally endorsing the establishment of the University of Lucerne.

In 2005, the Federal Council decided to recognise the University of Lucerne as a Swiss university in accordance with the University Promotion Act. In September 2011, the University of Lucerne moved into its new headquarter at Frohburgstrasse 3, right next to the railway station and the KKL.

The "Yes" vote in the November 2014 referendum on the revision of the University Act paved the way for a fourth faculty, the Faculty of Economics and Management. The latter commenced operations in the 2016 autumn semester.

A further milestone was the launch of the new Department of Health Sciences and Medicine, which reported directly to the President, at the beginning of August 2019. The revision of the University Act, which came into force on February 1, 2023, transformed the new department into a faculty. Meanwhile, a new Faculty of Behavioural Sciences and Psychology was established.