The church was built when the arrabal (suburb) of Santa Cruz was established by the Jesuits in the early 17th century.

[2] The Jesuits built the first Catholic church in the area where the present Santa Cruz Parish stands on June 20, 1619.

The original structure of the church was twice damaged by earthquakes and then completely destroyed during the Battle of Manila during World War II.

[7] On June 3, 2018, it was officially raised to an archdiocesan shrine by the decree of the then-Archbishop of Manila, Cardinal Luis Antonio Tagle.

[6] The church façade is characteristically Mission Revival with Ionic piers vertically dividing the first two levels in three parts.