Inauguration of Università Cattolica del Sacro Cuore took place in Milan on 7 December 1921 with a mass concelebrated by Father Agostino Gemelli and Cardinal Achille Ratti, Archbishop of Milan, who was to become Pope Pius XI three months later. The first seat of the university was in the Canonica Palazzo, Via Sant'Agnese 2. In October 1932, the university's seat was moved to the historic Saint Ambrose Monastery where it has remained to this day. In 1921, there were 68 students enrolled on the first two courses: Philosophical Sciences and Social Sciences.
The Italian government officially recognised the university in 1924, thereby allowing it to issue legally valid degrees and diplomas (the statutes of Università Cattolica were approved by royal decree on 2 October 1924, and were published on 31 October 1924 in the Official Gazzette of the Republic of Italy). The Faculty of Arts and Philosophy and the Faculty of Law were established soon thereafter, and the Higher Institute of Education originally set up in 1923 became an independent faculty in 1946, later in 1996 to become the Faculty of Education. The School of Social and Economic-Policy Sciences was separated from the Faculty of Law in 1926, and in 1931 became the Faculty of Political, Economic and Commercial Sciences, which also awarded degrees in Economics and Business until 1947. In 1936, the Faculty of Political Sciences became a separate entity.
Cattolica's commitment to education was again very evident immediately following World War II, with the creation of new programmes and the opening of additional campuses. In 1947 the university officially inaugurated the Faculty of Economics and Commerce, which also offered an evening course. On 30 October 1949, Luigi Einaudi, the then President of the Republic attended a ceremony at Università Cattolica to mark the beginning of construction for the Faculty of Agriculture in Piacenza, while the degree programme officially got started in November 1952.
A government decree was issued on 4 August 1958 providing for the institution of the Faculty of Medicine and Surgery in Rome. Adding a faculty of medicine had always been Father Gemelli's great dream (the founder was in fact a graduate of medicine and surgery from the University of Pavia). The undertaking proved demanding and complex, and in fact first had to wait many decades for the construction of the biological institutes and general hospital (later to be named after Father Gemelli). Construction work on the faculty buildings began in 1959, and Pope John XXIII celebrated a Mass on 5 November 1961 to officially open the Faculty of Medicine and Surgery. The first doctors graduated from the new medical school in 1967 by which time there were two degree programmes: Medicine and Surgery, and Dentistry.
In 1965 Università Cattolica opened its campus in Brescia, with a teacher training college drawing on the city's rich tradition of education. The Faculty of Mathematical, Physical and Natural Sciences was added in 1971, at the initiative of a group of renowned experts from the world of mathematics.
During the 1990s, three new faculties were added to the Milan campus: the Faculty of Banking, Finance and Insurance Sciences (in 1990); Languages and Foreign Literature, which is today the Faculty of Linguistic Sciences and Foreign Literatures (in 1991) and the Faculty of Psychology (in 1999). The Faculty of Economics at Piacenza, which had been a satellite of the Milan campus, became an independent faculty in 1997. Then in 2000 the Faculty of Law at Piacenza, which had been offering a degree programme since 1995 as a satellite of the Milan campus, also became independent of the Milan campus. The Faculty of Sociology was set up in Milan during the 2001-2002 academic year, and is Cattolica's fourteenth faculty.