It was most probably built by the architect Vittorio Cassar in 1580 as a monument to the Christian Victory after the Great Siege of 1565.
Senglea became a parish in 1581, and was consecrated on 20 October 1743. On 21 May 1786, Pope Pius VI declared the church to be a “collegiata insignis” (distinguished collegiate church), while in 1921, Pope Benedict XV honoured the church with the title of Basilica. After the crowning of the statue of the Virgin Mary on 4 September 1921, the church became a sanctuary of the Virgin Mary.
The church was destroyed by bombs in 1941, but was rebuilt and consecrated by Archbishop Gonzi on 24 August 1956.