Davis-Monthan Air Force Base was originally established as an important transcontinental municipal airport, Davis-Monthan Airport, at one time the largest municipal airport in the USA. Davis-Monthan was named in honor of two Tucson pilots and World War One veterans killed in separate military air accidents. Many coast-to-coast flights stopped at Davis-Monthan for refueling and servicing, including such aviation notables as Charles Lindbergh, Amelia Earhart, military aviation pioneer and later General and Chief of Air Corps Benjamin Foulois, and later Medal of Honor recipient General Jimmy Doolittle.

World War Two saw the acquisition of Davis-Monthan Airport in 1940, and temporary renaming to Tucson Army Air Field until the name reverted to Davis-Monthan Army Air Force Field slightly before the Pearl Harbor attack in 1941. Davis-Monthan Field was used as a vital continental link and heavy bomber crew training site, until the Axis Powers surrendered in 1945. Davis-Monthan rapidly reduced operations, ending bomber training and housing German POWs pending repatriation, July 1945 to March 1946. Unlike many airfields after the war, Davis-Monthan continued in service, first as a service separation center, then as a primary aircraft preservation and storage site, an aircraft "boneyard."

In 1948 Davis-Monthan was renamed Davis-Monthan Air Force Base, and given a new role housing the 43rd Air Refueling Squadron, the first air refueling unit in history. Davis-Monthan AFB continued it role as a bomber base from the late 1940s, into the Jet Age. In later decades Davis-Monthan also hosted strategic missile units, as well as support fighter wings, tactical fighting wings, and tactical fighter training wings. Notable among these tactical fighter units was the 355th Tactical Wing, the first unit flying the A-10 Thunderbolt IIs, a famous close air support fighter known as the A-10 Warthog. The 355th Wing played an important and effective role in Operations Desert Shield, Desert Storm, and Southern Watch.

In the 2000s, units based at Davis-Monthan AFB have provided direct combat and support missions for Operations Iraqi Freedom, Enduring Freedom, and Noble Eagle.