It was founded in 1638 (with the name of Giardino dei Semplici), with an ordinance of the University of Messina, by Pietro Castelli: he was from Rome, pupil of the famous scientist Cesalpino, teacher of philosophy and medicine at the archi-gymnasium of Messina. Already director of the Orti Farnesiani of Rome, he was sought after by Padua, which wanted him for their University. The land was given by the Senate, who paid for its construction. It was placed at the back of Porta Imperiale, along the city walls. The botanical garden was the first in Sicily and one of the first and biggest (approximately 164 x 1837 feet) of the Western world. It was soon celebrated as a pure scientific monument, one of the most important of Italy for its original arrangement and its rich collections. Castelli himself described it in his work "Hortus Messanensis," printed in Messina in 1640: in it he describes with accuracy the cataloguing method, an original and advance way for that time; in fact he put the plants in 14 classes and gave an anti-Linnaean nomenclature (later the botanic A. Arrosto translated the catalogue in the Linnaean nomenclature). Pietro Castelli’s successor was Marcello Malpighi, founder of comparative histology and anatomy (it was here in Messina that he made the majority of his observations using a microscope). But this first Botanic Garden ended after the revolution against the Spanish reign in 1678. The Spanish reign, in fact, wanted to punish the city by destroying its cultural life to prevent further revolts and to take political control. Besides the suppression of all the secular privileges, the University was closed and the Botanic Garden destroyed.

In 1838 the University of Messina was opened again, but the Botanic Garden had to wait more than 50 years to begin again: the 29th of April 1889, the Municipality gave four hectares of land near the Portalegni stream to make a new Botanic Garden. Antonio Borzì headed the project. He was a very famous scientist all over the world, and he was a precursor to the study of the ontogenetic studies of many algae. But, unfortunately, a new disaster happened: the earthquake of 1908 caused many damages, but, even more serious, was the construction in that area of accommodations for the evacuees. Nowadays there is only a space of one hectare, and some rooms have been given to the Faculty of Law. The Botanic Garden, on Piazza XX Settembre, is still very vital to the city and a big interest: there you can find gigantic specimens of the rare Pinus Brutia, the Dracaena draco, arborescent ferns, the Tipuana from Bolivia and the Calodendrum of South Africa, the Sapindus (also called the soap tree), the lianas from Amazonia, and also the Papyrus from Nile and Ciane.