In 1922, Zeta Beta, now Tuskegee Alumnae Chapter, was established in Tuskegee, Alabama as the first chapter in the South. The name was later changed to Zeta Sigma at the 1925 Convention in Des Moines, Iowa, and to Tuskegee Alumnae in January 1976. Sigma Chapter, now Atlanta Alumnae, was chartered in 1924 in Atlanta, Georgia as the second chapter in the South. The name, Sigma, was transferred to Clark College in 1929. Alpha Beta, the third chapter in the South, was established in 1925 at Fisk University in Nashville, Tennessee. From these chapters the Southern Region had its beginning. The Southern Region holds the distinction of being the largest of the seven regions of the Sorority, with over 214 alumnae and collegiate chapters and with more than 25,000 members.

The Southern Region was formed in 1926 at the 8th National Convention of Delta Sigma Theta Sorority, Inc., which at that time included the states of Alabama, Florida, Georgia, Mississippi, North Carolina, South Carolina and Tennessee. In 1960, at the Sorority’s National Convention, a new region was created to facilitate service delivery for chapters in the mid-Atlantic states, and North and South Carolinas left the Southern Region to become part of the Sorority’s South Atlantic Region.