Before it became an Episcopal cathedral, St. Mary’s was a mission church, organized in 1857 by members of Calvary Episcopal Church on the semi-rural,  eastern fringe of Memphis, Tennessee, on a spot now considered to be part of Downtown. It became the cathedral church of the old statewide Episcopal Diocese of Tennessee in 1871 and later the cathedral of the Diocese of West Tennessee with the creation of the three dioceses within Tennessee in 1983. A small wooden Gothic structure was built on a lot located at the eastern edge of the city at Poplar and Orleans. It was the desire of James Otey, the First Bishop of Tennessee, that "free seats" and "openness to all" would be the policy of this church, built as a "house of prayer for all people." St. Mary's Church was officially dedicated on the following Ascension Day (May 13, 1858). 
Construction of its present English Gothic Revival structure began in 1898 and was completed in 1926.

St. Mary’s “Sisters’ Chapel” was built in the 1880s for the Sisters of St. Mary’s to use as the chapel for St. Mary’s Episcopal School, once housed at this location.  This sacred and beautiful chapel provides a perfect space for Children's Chapel, Adult Formation classes and worship services of all kinds.