It is named after the Portuguese Grand Master António Manoel de Vilhena, who built a fort on the island in the 1720s.

In 1643, during the reign of Grandmaster Lascaris, the Order of Saint John exchanged the island with the church for some land in Rabat and built a permanent Lazzaretto in an attempt to control the periodic influx of plague and cholera on board visiting ships.

[2] Between 1723 and 1733, a new star fort was built on the island by the Portuguese Grand Master António Manoel de Vilhena.

The fort has a magnificent quadrangle, parade ground and arcade, and once housed a baroque chapel dedicated to St. Anthony of Padua, under the direct command of the Order.

During the course of the 19th century, some incoming mail was fumigated and disinfected at the Profumo Office of the hospital to prevent the spread of diseases.

[7] Annual fireworks displays that can be viewed from Sliema are launched from Manoel Island in August each year.