[3] In 1871 during the post-Civil War Reconstruction era, a group of five Sisters of Mercy from Columbus, Georgia, began a small school known as the Academy of the Sacred Heart Jesus on the corner of 4th and Walnut streets in Macon.

With help from others, the Sisters purchased the former home of Georgia Governor George W. Town for use at the corner of Orange and Columbus streets on Beall's Hill in downtown Macon.

The fall of 1963 marked the racial integration of Mount de Sales as a result of a diocesan edict, making it the first school in Middle Georgia to desegregate.

Cavalier Fields, a 77 acres (31 ha) athletic complex, opened in 1998 approximately 7 miles (11 km) west of the downtown campus.

In 2015, the school underwent $1 million of enhancements to align with redevelopment changes in Macon's College Hill Corridor, a two-square mile area between Mercer University and the downtown business district.

The middle school's House System places students in cross-grade level groups to foster positive social development.

[6][7] In 2014, the school's administrators fired Flint Dollar, an openly gay music teacher who planned to marry his longtime male partner, based on the Catholic church's doctrine against same-sex marriage.

[10] Mount de Sales competes in a number of interscholastic athletics in Class A of the Georgia High School Association (GHSA), where it previously was a member from 1961 to 1980.