After the inquisition was abolished during the French occupation of Malta in 1798, the palace was used for a number of purposes, including as a military hospital, a mess hall and a convent.

The palace was built in around the 1530s, and it initially housed the Magna Curia Castellania Melitensis, a tribunal which was established by Grand Master Juan de Homedes y Coscon in 1543.

[4] The building's original design is attributed to the architects Diego Perez de Malfreire[5] or Nicolò Flavari.

Grand Master Jean de la Cassière offered the former Castellania to Dusina as his official residence, who moved in after the building was renovated.

[10] Between the late 16th and 18th centuries, the various inquisitors who lived and worked in the palace made a number of major alterations to the building, and it was gradually transformed into a typical Roman palazzo with some Baroque influences.

The palace was enlarged with the acquisition of nearby properties, and the first major renovation began in the 1630s under inquisitor Fabio Chigi (later Pope Alexander VII).

It was initially used as a military hospital, and it was converted into a mess-house for officers stationed at the barracks near Fort Saint Michael in nearby Senglea.

The Public Works Office made plans to demolish the palace and replace it by government apartments in 1908, but nothing materialized.

[17] The Inquisitor's Palace was passed to the Museums Department in 1926, and an extensive restoration was carried out by Vincenzo Bonello and Antonio Sciortino until 1939.

[19] Apart from exhibits relating to the inquisition, the museum's collections also include a number of wooden architectural models of destroyed landmarks, including representations of Birgu before the World War II bombings,[20] the Order's bakery in Valletta before it was demolished in the 1930s,[21] and the Manderaggio before it was rebuilt in the 1950s.