The local Studiorum Universitas was formally established by Pope Paolo III in November 1548, although the city of the Strait boasts an ancient cultural tradition as well as a teaching tradition connected to a law school in the late XIII century and a well-known Greek school in the XV century.
However, the regular working activity of the Athenaeum was paralysed by the disputes that meanwhile had arisen with the Jesuits, (in order) to avoid them to control the monopoly over the Universities of the whole island.
It actually began its activities only in 1596. It was the beginning of a short as much as intense existence which ended in 1678, when the Athenaeum was closed as a result of the anti-Spanish insurrection.
During these years the University of Messina, closely linked to the city, represented the most symbolic political and cultural expression and reached high levels, including Giovanni Alfonso Borelli, Pietro Castelli, Giovan Battista Cortesi, Carlo Fracassati, Giacomo Gallo, Mario Giurba, Marcello Malpighi and Francesco Maurolico among its lecturers. After a long period, during which the advanced studies were given at the local Carolina Academy, the Athenaeum was refunded in 1838 by King Ferdinando II. In 1847 it was closed again because of the antiborbonic revolt of the city.
It was reopened two years later, but restricting the enrolment of students from Calabria and other Sicilian provinces. This was a severe measure, considering the Athenaeum’s students composition. In 1862 the University of Messina faced the downgrading to second class Athenaeum, and thanks to an agreement promoted by the Provincial council, the Town Hall and the Chamber of Commerce and Arts, it regained the title of first class Athenaeum in 1885.
Students, largely coming from the near Calabria, were not very numerous and between 1890 and 1908 the average of enrolled students ranged between 650 and 700 units. The University included numerous prominent lecturers such as Pietro Bonfante, Leonardo Coviello, Vittorio Martinetti, Vittorio Emanuele Orlando, Giovanni Pascoli and Gaetano Salvemini, even if, as an eminent and impartial observer stated, “many of them felt a burning wish to leave the Athenaeum as soon as possible, as it made difficult every profitable and serious scientific work for the lack of means and facilities.”
The earthquake of 1908 made the situation even worse.
Fourteen out of the forty-nine lecturers died under the ruins, while the majority of libraries and scientific facilities were destroyed. This occasion seemed as an opportunity to close the University of Peloritans, which was considered useless and expensive, and replacing it with professional and commercial secondary schools. The debate was rather heated and continued even after October 1909, when the Faculty of Law was reopened.
The restart was rapid and the rector Giovanni Maria Rizzo, starting up the academic year 1911-1912, stated "with satisfaction and rightful pride" that, even though the precarious conditions of the building was unsafe, courses were carried out regularly and the enrolled students were 219,190 attending the Faculty of Law and 29 attending the Faculty of Letters and Philosophy.
During the years 1914/1915, the Faculty of Sciences, Pharmacy and Medicine reopened among outstanding controversies.
Between 1919 and 1920 all the courses of the Faculty of Medicine were carried out thanks to the local institutions, which approved the establishment of a consortium managing the Civil Hospital where clinics had a temporary location.
In the same year, the University of Messina proved the recovering of its dynamism regaining the title of Athenaeum of the Strait, with a total of 1,221 students: 508 native of the province capital and 713 coming from the other Sicilian provinces and from Calabria. In 1922, the Rector Rizzo had the serious duty to prevent a proposed fusion with the University of Catania, advanced by the fascist regime. By that time, the Athenaeum strengthened its buildings and played a major role in cultural events of the country, overcoming the difficult period of reconstruction after the war, thanks to the rectors Gaetano Martino and Salvatore Pugliatti.