This is the mother church of Catholicism in the Carolinas and Georgia.  The small group of (mainly Irish) Catholics in the city had petitioned Bishop John Carroll of Baltimore for a priest as early as 1785. In 1786 Mass was celebrated by an Italian priest from a passing ship for twelve people at the home of a prominent Irish Catholic. 

Careful to find the right man for the new republic's "most polished and improved place", Bishop Carroll eventually sent a Dublin priest, Fr. Matthew Ryan, in 1788. In 1789 the congregation took over a small wooden church previously used by Methodists. Fr. Ryan was succeeded briefly by Fr. Timothy Keating, also from Dublin, and after a two-year gap, by a noted academic of similar origin, Fr. Simon Felix Gallagher in 1793. 

Fr. Gallagher, who also functioned as a principal instructor and administrator at the fledgling College of Charleston, raised funds to build a handsome brick church on this site by 1806. A dispute between Irish and French interests in the parish persisted until 1818, and Fr. Gallagher was often absent due to personal differences with the Baltimore prelates who were his superiors, and attempts to secure outside mediation in the troubled community.

The Jesuits Joseph-Pierre de Cloriviere and James Wallace were at one time deputed from Washington to minister in the parish but the agitation was only ended when a mission to Rome, led by the Irish Augustinian Fr. Robert Browne, resulted in the creation of a new diocese and the appointment of Bishop John England in 1820.

St. Mary's burned in the 1838 fire and was replaced by the present church, for which the contractor was Christopher Kane. Former pastor Dr. James Andrew Corcoran is commemorated in a notable ceiling mural by the decorative painter Chizzola.  

The stained glass windows are by the Munich firm of Franz Mayer & Co.  The churchyard contains graves of 18th- and 19th-century immigrants of Irish, French, Italian and Spanish origin.