Holloman AFB was established as Alamogordo Air Field, near Alamogordo, New Mexico, USA, in 1942, originally intended as a British Commonwealth training center for the pilots from the Royal Air Force and the Royal Canadian, Royal Australian, and Royal New Zealand Air Forces. Various factors, including the sudden entry of the US into World War Two, shifted British and US interests and by the time the field was completed, in June 1942, it entered service as Alamogordo Army Bombing and Gunnery Range, renamed Alamogordo Field Training Center within weeks, and then redesignated an Army Air Base a few weeks after that.

Regardless of name, Alamogordo trained bomber crews for the B-17 Flying Fortress and Consolidated B-24 Liberator aircraft for service in overseas. Over 20 bomber groups were trained at Alamogordo and posted over the course of the war. With the end of the war, Alamogordo was initially slated transfer its training mission and become a permanent B-29 Stratofortress base, but budget cutbacks prevented this and the base was inactivated.

Rumors of permanent closure flew, but the base was reactivated and assigned to research and development programs, including some of the earliest tests of pilotless aircraft, precursors of modern UAVs; for many years the base was mainly dedicated to research and development of guided missiles, and the was the Air Force Missile Development Center base for 25 years. The base was renamed Holloman Air Force Base in 1948, after Col. George V. Hollowman, guided missile and pilotless aircraft pioneer. Over the course of the Cold War, many US Air Force guide missile systems were developed at Holloman, as well as other interesting projects. Missiles developed at Holloman include the first Army rocket, the Tiny Tim, the Rascal, testing and evaluation of the captured German V-2 rocket, the Falcon, the MGM-13 Mace, the MGM-1 Matador, and the AGM-45 Shrike. Other military systems developed at Holloman include inertial guidance systems, radar target scattering research, and target drone systems.

Famous testing and training projects at Holloman included was the new land speed record set by Lt. Col. John P. Stapp, M.D., in the Sonic Wind 1, a rocket test sled; Lt. Col. Stapp earned the nickname "The Fastest Man Alive" with his record breaking 632 mph ride, in December 1954. In August 1960 Capt. Joseph W. Kittinger, Jr. set four records with his highest open gondola manned flight, highest balloon flight, highest bailout, and longest free fall jump, falling 102,800 feet for 13 minutes at a drop speed of 614 miles per hour, as part of Project Excelsior. All but the longest fall records stood until 2012. Another interesting project at Holloman AFB was the training of the space chimps Ham and Enos, who became the first two chimpanzees in space, as part of testing for the US space program.

Holloman has also housed tactical fighter units over the decades, including the 366th Tactical Fighter Wing, the 49th Tactical Fighter Wing, and 479th Training Wing. Currently Holloman's host unit, the 49th Wing, flies F-22 Raptors, air transportable medical clinics, and BEAR Base assets. Since 1996 Holloman has also served as host base for the German Air Force Tactical Training Center, housing about 650 Luftwaffe personnel and 25 Tornado fighter jets.