The Botanical Garden was established in 1779 to accommodate a small garden. The goal was the cultivation of "simple" medicinal plants, useful to teaching and public health.
Already in 1786 it was decided to transfer it to a more appropriate site, near Villa Giulia.

The construction of the main building of the Garden, in the neoclassical style, was completed in 1795.
It consists of a central building, the Gymnasium, and two lateral bodies, the Tepidarium and the Calidarium, designed by French architect Leon Dufourny.
Near the Gymnasium there is the oldest part of the Garden, the Linnaeus system.
Upon the recommendation of the Franciscan priest Bernardino Ucria, an outstanding botanical garden in this portion of the species was arranged according to the taxonomy of Carl Linnaeus.
In 1823 Serra Maria Carolina was completed. The large Ficus magnolioide, which is the symbol of the Garden, was imported in 1845 from Norfolk Island.

The scientific collections have a consistency estimated at more than 12 000 species. The biggest part of them come from plants originating where the subtropical climate has many characteristics in common with that of the Sicilian coast.
In the early years of the existence of the Botanical Gardens, the rapid growth of plants imported in bulk from Africa, America and especially Australia, colonized in a continuous spiraling growth.