After the Texas War for Independence, numerous immigrants, notably from Ireland, Germany, and the Eastern United States, arrived in San Antonio. The need to minister to these non-Hispanic Catholics prompted the Rt. Rev. John M. Odin, first Bishop of Galveston, to establish a separate church for them.
In 1852 land at this site was purchased from the heirs of Ambrocio Rodriguez, a veteran of the Battle of San Jacinto. In 1855 Bishop Odin authorized a building project, undertaken by the Rev. J.M. DuBuis, who became first pastor of St. Mary's Parish and later second Bishop of Galveston. A stately Gothic church building was constructed and opened for worship in mid-1857, serving both English and German-speaking congregations. (In 1869 St. Joseph's Church assumed the ministry for the German Catholics.) On July 1, 1884, the Oblates of Mary Immaculate accepted responsibility for St. Mary's, with the Rev. Richard J. Maloney as first oblate pastor.
The old church building was also the site of a seminary, an early free parochial school, the publication of a major Catholic newspaper, and the founding of the St. Vincent de Paul Society.
In 1921 flood irreparably damaged the church building. This Neo-Romanesque structure was dedicated in 1924.