Located in Houston's midtown area, the church has a long history in the city.

Sanguinet, Staats, Hedrick A and Gottlieb were hired to design the new structure in 1924 for the then Tuam Baptist Church.

[2] The church moved to its current location when the new building was completed in 1930.

It was a member of the Southern Baptist Convention for over 90 years, but has now withdrawn.

South Main Baptist Church assisted in the creation of Operation San Andres, a non-profit group that feeds orphans in Peru.