The first official reference to this district is on December 8, 1863, when Colonel Edward Dillon was assigned to command it. There was no clear definition of its boundaries other than "the region south of Brigadier-General [William H.] Jackson's command and west of the Department of the Gulf." Brigadier General Thomas H. Taylor replaced Dillon on March 5, 1864. He in turn was replaced by Colonel John Scott on April 12. Hodge signs as commander on June 26. Brigadier General St. John R. Liddell was commander on August 2. The boundaries were described as "the country south of a line running due east from Natchez to the Pearl River," so all Mississippi counties in that area would have been included. All of the Louisiana parishes east of the Mississippi River were in the district. Hodge relieved Liddell on August 4. On August 29, Hodge called his command the District South of Homochitto.

The Department of Alabama, Mississippi, and East Louisiana, to which the district belonged, underwent several reorganizations. One of these occurred on October 12, 1864. The District of Mississippi and East Louisiana (which included all of Mississippi and the Florida Parishes of Louisiana) was divided into sub-districts. One of these was the Sub-District of Southwest Mississippi and East Louisiana. It was to "comprise that portion of the State of Mississippi south of the parallel of latitude running through Natchez and not included in the District of the Gulf [which would have been the coastal counties] and the portion of Louisiana east of the Mississippi River." Hodge retained command of the sub-district. On February 3, 1865, the sub-district was redesignated as the District of South Mississippi and East Louisiana. Its boundaries were defined as "all that portion of the State of Mississippi not included in the District of North Mississippi and West Tennessee, or the district of the Gulf." The District of North Mississippi and West Tennessee included "all that portion of Mississippi north of the counties of Nuxubee, Winston, Attala, Holmes, and Washington." Brigadier General Wirt W. Adams assumed command of the District of South Mississippi and East Louisiana and seems to have held command of it until the end of the war.