Keesler AFB was proposed by Biloxi, Mississippi, city officials to the US Army in January 1941, as a site for an Army base, as part of the Federal government's preparation for an expected entry into World War Two. The original proposal was for a technical training center, but the site was appealing enough to not only situate the technical school, for aircraft and engine repair, radio operators and aviation technicians, but also a basic training center, and pre-aviation cadet school. The original estimate for the Army base was about 5,000. When the US did enter World War Two, the population of Keesler hit around 20,000, and kept growing. The base was named from the beginning after 2nd Lt. Samuel Reeves Keesler, Jr., a Mississippi native and aerial observer KIA in World War One.

Recruits arrived at Keesler for a four week basic program, and were either selected for additional training at Keesler or selected for training at another center; many trainees went through their entire training at this base, although aerial gunnery and aviator training were not conducted here.

Notable among these trainees was the famous Tuskegee Airmen, an "all-colored" group of pilots and aircrews, formally the 332nd Fighter Group and 477th Bombardment Group. Despite considerable difficulties these groups formed what turned out to be an elite fighter escort squadron; the 332nd, particularly the 99th Fighter Squadron earned a deserved reputation as the Red Tails; the Red Tails had an exceptional escort record with a remarkably low bomber loss rate, and an exceptional overall unit combat record. In the later days of World War Two the inflow of recruits declined, and basic training was halted at Keesler. Technical training continued, but consolidated many facilities.

Keesler Army Base was transferred to the Air Force with the separation of Army and Air Force. Other technical schools were assigned to Keeler over the next 20 years, including radio operators, air traffic service technicians and air traffic controllers, ground radar mechanics and repairmen training, and missile ground support technicians. The end of the Vietnam War brought training class sizes to an all time low. The end of the Cold War brought additional training to Keesler, as a result of base closures and force reductions, with the transfer of the 53rd Weather Reconnaissance Squadron and its associated training programs to Keesler. Ongoing force changes has resulted in the inactivation of the Keesler Training Center and redesignation of Air Training Command to Air Education Training Command, housing the 2nd Air Force Headquarters, which oversees all AETC technical training. Keesler continues to train the Air Force for the future.

Keesler Army Base is the setting of Neil Simon's Biloxi Blues, a 1985 Broadway drama and later 1988 motion picture, loosely based on his own Army Air Force experiences. In real life, Keesler Air Force Base has been directly hit by two hurricanes, Camille in 1969, and Katrina in 2005.