Although the person who designed the Horto medicinale is not recorded, the architect Andrea Moroni from Bergamo was certainly involved in its construction.
The trapezoidal shape of the allocated plot of land influenced the design of the Garden, which was drawn as a circle containing a square, divided into four smaller squares by two main intersecting paths. The four squares, called "quarters", or "tiers" because they were originally about 70 centimetres higher than the paths, were divided into flowerbeds (areole), which were arranged to form a series of completely different, elegant geometrical patterns. In 1552, an enclosing wall was built to prevent continual night thefts of the precious medicinal plants grown in the Garden.
Later, the architectural structure of the Garden changed and was enhanced, but the original configuration was maintained.
In the early 1700s, the four large gates of the Hortus cintus were built with trachyte jambs surmounted by stone vases (acroteria) containing wrought-iron plants and enclosed by elegant iron gates.
The step previously existing between the paths and the "tiers" was levelled, and the design of the flowerbeds also changed. A fountain was built in the middle of each quarter, and another one where the two main paths intersect. In the first half of the 18th century, the circular wall was improved by adding a balustrade with fine white stone columns, vases, and busts of well-known people facing the centre of the Garden.