Under the Knights of St John and during the British period after 1800, passengers, irrespective of occupation, nationality or status who arrived in Malta, especially when plague and cholera were prevalent in Europe and the Levant, were kept for periods in quarantine, as detailed by the health authorities and kept under observation at the Lazaretto. Here their liberty was curtailed and they were forbidden to set foot in Malta and Gozo.

The quarantine laws were legally structured to be comprehensive and effective. To ensure that regulations were strictly adhered to, armed guards were employed to see that no incoming passengers left the Lazaretto. Furthermore, no Maltese were allowed to approach them. Letters were fumigated. After attending to passengers or sick members of ships' crews, doctors and health staff had to undergo quarantine themselves.

Plague and cholera brought misery, fear, chaos and disruption, so obviously the authorities did their best to avoid contagion. The tyranny of death was very real when plague and cholera broke out. For example, in the 1837 cholera epidemic, of the 8,735 persons affected, 4,250 died.

The most rigid enforcement of quarantine regulations was vital in the public interest. Disregarding them could entail the death penalty. At Manoel Island there used to be an inscription in Italian (the gallows to which it refers was removed years later on the instruction of the Superintendent of Ports), which in translation reads:

"The gallows were erected on March 26, 1814, for the execution of Felix Camilleri, one of the guards of the Lazaretto who had been condemned to death for having openly broken quarantine, but received a free pardon from His Majesty's Governor as having been the first individual sentenced to death after the sovereignty of these islands had been assumed by the Prince Regent on behalf of the King".

Following various epidemics over the centuries, saints' niches and altars were dedicated to the human tragedies. St Roque, St Basil and St Sebastian were venerated.

Persons who died at the Lazaretto were buried at Manoel Island, including at St George's Cemetery, erected in 1813. A ledger limestone slab, dated 1813, inscribed as Catavero infetto, was marked to indicate that the dead body inside had been infected with a contagious disease. This slab had been salvaged and now lies among other exhibits at the very interesting Maritime Museum in Vittoriosa.

During World War II, Manoel Island was severely damaged by air-raids. At one time some graves were burst open by explosions. A team of soldiers were ordered to dig a trench so that macabre-looking skulls and bones were buried again.