It occurred in three waves between June 1592 and September 1593, during the second plague pandemic, and it resulted in approximately 3000 deaths, which amounted to about 11% of the population.

Four galleys of the Grand Duchy of Tuscany or the Order of Saint Stephen had captured two vessels from Alexandria, and took their cargo and about 150 Turkish captives with them to Malta.

While en route to Malta, an outbreak of the plague began on board the ships, killing 20 crew members.

[7] After the outbreak became more severe in March, Grand Master Hugues Loubenx de Verdalle requested assistance from the Viceroy of Sicily, who sent the Pietro Parisi from Trapani, a doctor who had experience with contagious diseases.

Walls of houses with confirmed or suspected cases of the disease were washed with seawater and whitewashed with lime, and similar measures were undertaken in burial grounds.

[7] The epidemic began to subside by June 1593, and attempts were made to purify the island to remove any traces of the disease which might have been left.

[7] A number of small villages or hamlets lost most of their populations during the epidemic, and were later abandoned or absorbed into nearby settlements.

The outbreak began in the household of the Port Chief Sanitary Officer, and it is possible that it was caused by handling refuse from the earlier epidemic.