The Studiorum Universitas was formally established by Pope Paul 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 13th century and a well-known Ancient Languages school in the 15th century. However, the regular working activity of the Athenaeum was paralysed by disputes with the Jesuits, in order to prevent them from monopolizing the Universities of the whole island.
The University began its activities only in 1596. It was the beginning of a short but 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 represented a strong political and cultural influence. It reached high levels, featuring top professors including Giovanni Alfonso Borelli, Pietro Castelli, Giovan Battista Cortesi, Carlo Fracassati, Giacomo Gallo, Mario Giurba, Marcello Malpighi and Francesco Maurolico.
The Athenaeum was refinanced in 1838 by King Ferdinando II, but it was closed again in 1847 because of an Anti-Bourbon Revolt and reopened only 2 years later.After these years the University included numerous prominent lecturers such as Pietro Bonfante, Leonardo Coviello, Vittorio Martinetti, Vittorio Emanuele Orlando, Giovanni Pascoli and Gaetano Salvemini.
In 1908 an earthquake destroyed the city of Messina. Fourteen lecturers died under the ruins, while the majority of libraries and scientific facilities were destroyed. The University reopened in October 1909 starting with the Faculty of Law. During the years 1914-1915, the Faculty of Sciences, Pharmacy and Medicine reopened among outstanding difficulties.
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 recovery of its dynamism by regaining the title of Athenaeum of the Strait.
Year by year, the Athenaeum strengthened its buildings and was playing a major role in cultural events of the country, overcoming also the difficult period of reconstruction after World War II, thanks to the Rectors Gaetano Martino and Salvatore Pugliatti.