The parish was founded in 1858, and their original church was a simple brick structure built on part of the current lot, but the congregation soon outgrew it.

[6] Isaac Hecker, who founded the Paulist Fathers, may have had a hand in its design as well, using the thirteenth-century Cathedral of Santa Croce, Florence as a model.

[6] The granite for the stone entrance steps was salvaged from the French Second Empire-style Booth's Theatre on Sixth Avenue at 23rd Street.

The new building was dedicated on January 25, 1885,[7][8] but was still not complete at that time: the 114-foot (35 m) towers[9] had yet to reach their final height, and much of the interior declarations were still to be installed.

Lumen Martin Winter's Angel of the Resurrection adorns Hecker's sarcophagus, located in the northeast corner of the nave.

The New York Daily Tribune reviewed the architecture as "vast, plain, fortress-like in its solidity—almost repelling in the aesthetic cast without and within, yet it is the most August, unworldly interior of this continent.

When financial issues forced the Archdiocese of New York to close the school, St. Paul's established pre-school centers funded by Project Head Start under the Economic Opportunity Act of 1964, providing students with free lunches and medical and dental care.

The parish went through a financially difficult period in the 1960s and 1970s, with the possibility of bankruptcy in 1973, and razing the church for an apartment building was briefly considered.

[16] St. Paul the Apostle serves as the parish for Catholic students at nearby Fordham University, the John Jay College of Criminal Justice, and the Juilliard School.

The large church basement has been used as a cafeteria for the parish school, a homeless shelter, soup kitchen, rehearsal space for The Rockettes, and for boxing matches.