The founding Sisters were Magdalen Clark, Catherine McCormack, Vincentia Fitzpatrick, Ann Simpson Sr. Lucy Harper, and Emily Thorpe.

St. Agnes was situated in what were then the suburbs of Memphis (Vance and Orleans), about a mile and a quarter from Court Square, the center of the city.

On October 5, 1918, the faculty of St. Agnes established the Memphis Conservatory of Music where students could acquire a B.A.

It became the formal music education center of Memphis for beginning, advanced, and professional students.

After 100 years at Vance and Orleans, St. Agnes Academy moved to its present site on Walnut Grove Road (Barbara Daush Blvd) in 1951.

Completing the Early Childhood Center and Tot Lot in 1998 accommodated the earliest grades.

The opening of a multipurpose building, Siena Hall, in 1999 allowed the removal of all temporary structures and provided a pedestrian campus.

As of 2013[update], the School was operated as one entity by a board of trustees consisting of parents, local leaders, and representatives of the Dominican Sisters of Peace.

On August 5, 2022, St. Agnes-St. Dominic launched the "Go Light the World" campaign which consists of building a new STEM facility to replace the Buckman/Davis building built back in 1991, and a new athletic complex that will consist of a gymnasium that will hold a maximum of 650 seated spectators.

The new STEM facility was just recently completed while the new athletic complex still awaits construction and is expected to be finished by the conclusion of the 2024–2025 school year.