Dover AFB was originally the municipal airport for Dover, then called the Dover Airdrome. It was rapidly converted from civilian to military use with quickly constructed temporary buildings and housing, starting in March 1941 and ready for first unit assignments ten days after Pearl Harbor. The first units assigned to Dover were anti-submarine air patrol and anti-submarine attack bombers. As the threat of enemy submarines receded, Dover's facilities were upgraded and mission changed to operational training for the 83rd Fighter Group, flying P-47 Thunderbolts. Later in the war, Dover was the site of experimental air-to-surface rocket attack systems. Post war, Dover Army Air Base was inactivated from 1946 to 1950.

In 1950, the Korean War and growing Cold War created a need for additional bases for the expanded and now independant Air Force. Dover was reactivated, heavily modernized, and assigned fighter interceptors for defense of the Middle Atlantic East Coast. Over the years Dover became a medical center, air transport/airlift hub, and mortuary receiving center, eventually expanding to include housing for 1,200 service families. Dover AFB was the primary receiving center for the evacuees of Americans from Iran in 1978, and units from Dover have carried some unusual cargos over the years, including an air dropped and air fired Minuteman missile test, and delivering a 40 ton superconducting electromagnet to Moscow, in 1977, as part of a joint US-USSR energy research program.

Near the end of and following the end of the Cold War Dover continued as a major airlift and medical center, hosting cargo lifting operations for Operations Urgent Fury, Just Cause, Enduring Freedom, and Iraqi Freedom. Dover is also the main port of entry for US Armed Forces service personnel killed in action.