The origins of this Catholic church can be traced to an attap (thatched roof) chapel that was built in 1853 on Upper Serangoon Road, its congregation comprising mainly Teochew farmers living in Serangoon and Punggol. Subsequently, a brick chapel was built in the area and named St Mary's Church. Father Jean Casimir Saleilles, parish priest from 1881 to 1911, was responsible for building the present church in 1901.
Father Saleilles also helped to spread the Catholic faith to Johor. He founded the Church of Our Lady of Lourdes (Johor), later renamed the Church of the Immaculate Conception and subsequently designated a cathedral. His good relationship with Sultan Ibrahim of Johor led the Sultan to present the Church in Johor, as well as the Church of the Nativity in Singapore, each with a statue of the Blessed Virgin Mary. The Church of the Nativity's statue stills stands in front of the church building.
Architecturally, the Church of the Nativity was based on the Gothic designs of Father Charles Benedict Nain (who was also the architect of the Chapel of the Holy Infant Jesus and the façade of the St Joseph's Institution). The church was gazetted as a national monument in 2005.
The Church of Nativity founded many educational institutions in the region, including the Holy Innocents High School, Hai Seng Girls' High School, Convent of the Holy Infant Jesus Ponggol, and Montford School.