The original church was built upon the request of Giovanni Calamia to house the icon of Our Lady of Damascus brought over from Rhodes by the Knights of St John when they were expelled from the island by the Ottoman Empire.

In 1587 the Icon of Our Lady of Damascus was solemnly transferred from Vittoriosa to the new church.

[1] On March 24, 1942, during one of the bombings of Valletta, the Church of Our Lady of Damascus was hit and completely destroyed.

It was because of the initiative of Italo-Albanian Papàs Gjergji Schirò from Piana degli Albanesi, that the Church was rebuilt and reconsecrated on August 15, 1951 by Archbishop Georgios Halavazis.

[2] The church is mainly used by the Catholic community of the "Greek rite" of Malta for Divine Liturgy.