The building was built as a hospital in the 16th century by the Order of St. John, and it was known as the Sacra Infermeria or the Holy Infirmary (Maltese: Il-Furmarija).

[2][3] It was known as the Grand Hôspital during the French occupation of Malta[4] and during the British period was named as the Station Hospital.

The Holy Infirmary was ordered to be built by Grand Master Jean de la Cassière on 7 November 1574, after a Chapter General, to replace the one in Birgu.

[9] It was meant to receive Maltese and foreign patients, as well as to provide lodging to pilgrims travelling to the Holy Land.

During the reign of Grand Master Raphael Cotoner, the infirmary was enlarged, with more wards added.

This work continued until 1666, during the reign of Raphael's successor and brother, Nicolas Cotoner.

When the French, under Napoleon Bonaparte, occupied Malta in 1798, they made alterations to the hospital.

[12] The Sacra Infermeria is listed on the National Inventory of the Cultural Property of the Maltese Islands.

[6] On 20 November 2016, the centre was the official venue for the Junior Eurovision Song Contest of the same year.

It also held the 2016 Malta Eurovision Song Contest earlier that year in January.