The school began as St. Mary's Institute on March 25, 1852 in rented rooms above a blacksmith's shop on Military Plaza.

[6] The original faculty consisted of Brother Anthony Edel (Founder, First Superior, and First Principal) from Ohio, three Marianist Brothers from Bordeaux, France (Nicholas Koenig, Jean-Baptiste Laignounse, and Xavier Mauclerc), and Timothy O'Neil, a layman from San Antonio.

[7] The site is now a hotel entryway, recognized by Texas Historical Marker #3819[8] as the location of Old St. Mary's College, or "The Old Academy."

[13][14] The school expanded in 2013 with the addition of a new library and eight new classrooms attached to the main building, comprising 16,370 sq ft (1,520 m2).

[9] In 2019 the 40,000 sq ft (3,700 m2) Kahlig-Cowie Convocation Center & Mother Adele Chapel opened, providing space for athletics and faith.

[15][16] Central Catholic is one of the oldest high schools in San Antonio, and it counts many prominent business and political leaders among its alumni.