Originally built by the Order of St John as a gunpowder store in circa 1665, by the 1700's the site became Malta's first home for the elderly. Then, under British rule, the site also served as as a female prison, as well as a refuge for illegitimate and stray girls. It remained a state multipurpose institution till 1892.

The Ospizio was originally well decorated, with a fountain and an accompanying artistic statue (which at some point simply disappeared overnight) embellishing the far wall of the Ospizio's open space.

One of the more famous prisoners held at the Ospizio was Margaret Semini, the Maltese wife of Englishman George Dalzel, who was imprisoned for adultery in 1840. Historian Giovanni Bonello writes that "We do not know how long Dalzel paid for his wife to remain in prison. If his was a vindictive disregard of money, he could have left her there for her whole lifetime." Malta eventually decriminalised adultery in 1972.