The origins of our University date back to around 1175, when Pillio da Medicina, a Lawyer active in Bologna, was invited to Modena by the ruling elite of the Municipality to open a school of legal education focused on Roman law. It is therefore one of the oldest universities in Europe, after Bologna and Paris. Formal recognition (the name Studium) came through a 'brief' by Pope Honorius III, whereby the bishop of Modena was endowed with jurisdiction over the scholars in 1224. Several generations of lawyers took turns at teaching, including some of the most prominent, such as Uberto from Bobbio, Omobono Morisi from Cremona, Martino del Cassero from Fano, Guido from Suzzara, Alberto Galeotti from Parma, the Frenchman Guglielmo Durante and Niccolò Matarelli from Modena. In the meantime, in Reggio Emilia, unofficially, between the 11th and 12th centuries, there were active law schools led by prominent personalities such as Jacopo Colombi, Accursio from Reggio, Jacopo d'Arena, as well as the aforementioned mentioned Uberto from Bobbio, Omobono Morisi and Guido from Suzzara. 

Despite the richness of university life, documented among other things by the existence of a College of Doctors and a Universitas scholarium (the students' corporate association), the advent of the Este dominion at the beginning of the 14th century led to an irreversible crisis, culminating in 1391, the year when the University of Ferrara was founded, when all Este subjects were forced to pursue a degree. 

In Modena and Reggio, however, there were still some active private Academies, that prepared students for obtaining a PhD in Ferrara, allowing a certain continuity of cultural life and specialised training. 

After 1598, the year of Ferrara’s ‘devolution' to the Papal State, the project to reopen the Studium took shape in Modena, the new capital of the Duchy. After several attempts by the municipality to finance the departments, also thanks to the contribution of charitable works and private donations, it was not until 1682, at the College of the Congregation of St Charles, that the first academic year of the renewed Athenaeum could begin. On that occasion, the opening speech was read by Bernardino Ramazzini, the physician from Carpi universally considered to be the founder of occupational medicine. Duke Francis II, although he did not finance the initiative, issued in 1685 those Statutes that were considered necessary to give the public Studio di San Carlo the rank of University, that is, of an institution capable of providing a recognised degree also outside the small duchy. 

The renewed college began its activities with eight chairs: three in Philosophy (Logic, Physics, Metaphysics), one in Medicine, two in Law (Institutions and Civil Law), two in Theology (Moral and Scholastic), and others were later added: Mathematics, Canon Law, Feudal Law, Hebrew and Greek language, two more chairs in Medicine, and a second chair in Theology. The institution was strengthened by initiatives carried out by Don Cristoforo Borghi (1601-1677), a native from Formigine, who in his last will arranged some lectures to be held at the University. Among the most illustrious lecturers of this period were Francesco Torti, a distinguished clinical physician and anatomist, Lazzaro Spallanzani, a well-known naturalist, and Giovan Battista Venturi, a physicist with multifaceted interests. 

Lastly, by the time they were in a reform era, two initiatives are worth mentioning due to endowments specifically set up by lawyer and minister Giuseppe Maria Bondigli, who was strongly influenced by his friend Ludovico Antonio Muratori, who were both graduates of the Modena College: with the first, in 1757, the chair of Criminal Institutions was created; with the second, in 1768, that of Public and common Law, held by the lawyer Bartolomeo Valdrighi, one of the main creators of the 1771 code. 

In 1772, Duke Francesco III carried out an important university reform that, like other Italian and European initiatives, gave the University the task of specialised training for the new ruling class, assuming direct control of its operation and finally providing funding. The high calibre scientists Michele Rosa and Antonio Scarpa, both doctors, were called to teach in Modena. 

The University also ran a two-year preparatory 'philosophical' course. The inauguration took place on 25 November 1772, with a speech held by Agostino Paradisi, president of the philosophical class and one of the first professors in Italy (after Antonio Genovesi and before Cesare Beccaria) to teach Civil Economics. 

In the same span of time, the Botanical Garden (1758), the Anatomical Theatre at the Grand Hospital (1773-75) as well as the Natural History Museum (1786) were created at the ducal gardens. 

Francis III's attempt in 1753 to provide the city of Reggio with an autonomous university institution, in homage to the imperial privileges of doctoral conferral granted to the College of Lawyers in 1531 and the College of Physicians in 1571 as well as the fruitful experience of the seventeenth-century Academies and Seminary Schools, was contradicted by the general reform of the University of Modena implemented, as mentioned, in 1772, although it may be an interesting first precedent of what was to become, almost 250 years later, a networked university model. The years of French occupation and then submission to the Italian Republic (1802) led to the University's closure, as it was transformed into a departmental high school, just as Giuseppe Luosi, who graduated in law in Modena, became Minister of Justice for the Napoleonic Kingdom of Italy. 

The University was re-established in 1814, with the return to Modena of the Este family, who, however, despite the presence of high-profile professors, such as the mathematicians Paolo Ruffini and Antonio Araldi, as well as the physicist and optician Giovanni Battista Amici, always viewed free teaching with suspicion. In 1821, when the first student uprisings of Carbonari origin took place, the Faculty of Law was closed and split into four boarding schools distributed throughout the duchy. The boarding school experience was also introduced for doctors and aspiring engineers, who in 1823 gathered in the Boarding school for Cadets of the royal Corps of pioneers (the former Napoleonic School of Engineering), under the guidance of a colonel. However, these tensions did not prevent the endowment of further facilities: the Cabinet of Medical Matters (1816), the Zootechnical Museum and Astronomical Observatory (1827), the Zoo Institute (1842). Even after another dramatic break - the 1848 uprisings - significant developments took place, such as the establishment of a Veterinary School and, in 1849, the removal of the two-year preparatory course for university admission from Jesuit control.

With the unification of Italy, following the first rectorship of Francesco Selmi, the university began facing its first difficulties—challenges common to all institutions considered of lesser importance, as the new state sought to reduce its financial commitments. As early as 1862, the reform introduced by Minister of Public Education Carlo Matteucci established a distinction between "major" and "minor" universities (also affecting faculty salaries), which soon led to the threat of a complete withdrawal of state financial support. Modena reacted to this situation by creating a Consortium in 1877, whereby a number of city institutions (Municipality, Province, Savings bank, Charity Congregation) set up a fund to cover part of the university's operating expenses. This initiative, along with other similar ones undertaken throughout Italy, formed the basis of the law of 14 July 1887, which placed the University of Modena, along with those of Parma and Siena, on equal footing with the 'major' seats.

After yet another attempt, this time pursued in 1893 by Minister Ferdinando Martini, to suppress several universities, including Modena, in 1923 - the exact year in which Sandro Pertini graduated from Modena - Decree no. 2102 went into effect on September 30th 1923, the so-called Gentile reform, which, among other novelties, reintroduced the distinction between class A and class B universities. The University of Modena was sidelined once again to the latter and it was deprived, furthermore, of the Higher School of Veterinary Medicine and the two-year preparatory course in Engineering, which was later reinstated in 1936.

Again in this case, after a decade of bitter claims, which saw the establishment in 1929, initiated by the Dean Pio Colombini, a Permanent Commission for the History of the Royal University of Modena, which led to the law no. 1071 of 20 June 1935, that finally abolished the hateful discrimination. 

After the war and with the advent of the Republic, the University of Modena underwent a profound process of reorganisation and revitalisation, led by prominent figures such as Giuseppe Dossetti, who was involved in drafting the Republican Constitution and served as a professor of Canon Law in Modena. Notable milestones from this period include the establishment of the Institute of Forensic Application in 1948, the introduction of the degree programme in Geological Sciences in 1958, followed by Biological Sciences in 1959, the founding of the Policlinico in 1963, and the creation of the Faculty of Economics and Business in 1968. 

In the 1970s, the University of Modena comprised five faculties (Law; Medicine and Surgery; Mathematical, Physical, and Natural Sciences; Pharmacy; and Economics and Commerce) and 20 specialisation schools within the Faculty of Medicine. Additionally, it housed several specialised centers, including the School of Obstetrics, the School for Cardiology Technicians, the Supplementary Course in Practical Hygiene, and the Oncology Center within the Institute of Radiology. In 1990, the university inaugurated its sixth faculty, Engineering, completing the already existing two-year preparatory programme.

In 1998, the University of Modena adopted the name University of Modena and Reggio Emilia, structuring itself according to a network-based campus model, a rare example in Italy. This model is characterised by a complementary development plan, unified management, and equal status of the academic centres. At the same time, new faculties were established in Reggio Emilia, including Communication Sciences, Agriculture, and a second Faculty of Engineering, while in Modena, the Faculty of Humanities and Philosophy was inaugurated.

Further significant changes were implemented in compliance with the law no. 240 of 30 December, the so-called Gelmini reform, which, among other novelties, put an end to Faculties, giving rise to an articulation of universities into Departments and Schools.