McGuire Field began as Rudd Field, the airfield for Camp Dix, New Jersey. Rudd Field was upgraded to Fort Dix Army Airfield in 1939 and greatly expanded from 1940 to 1941. The first aircraft unit at Fort Dix, the 59th Observation Group, took up residence in November 1941, just less than a month before the entry of the US into World War Two. The mission of the 59th was to patrol for submarine raiders operating against British and soon American shipping; the 378th Bombardment Group provided bomber escorts, a mission handed over to the US Navy in 1943. Fort Dix AAF also conducted training for flight and base support services, including mail, runway, ground control, fire fighting, security, weather prediction, ground gunnery instruction, and ground transport.

In 1943 the Air Transport Service Command took residence at Fort Dix AAF, preparing aircraft for transfer to service in North Africa and Europe; at the end of the war, the ATSC reversed the job, receiving aircraft and aircrew back from overseas duty. In late 1945 the field was inactivated.

In 1948 the field was reactivated as McGuire Air Force Base, named for Major Thomas McGuire, Medal of Honor recipient and combat ace, one of the most highly decorated pilots of World War Two, under Strategic Air Command. A modernization program converted the World War Two temporary buildings into long term base facilities, including improved runways for jet aircraft, permanent housing, and general repair of hangars and fuelling facilities. One of the first units located at McGuire was the 91st Strategic Reconnaissance Wing, flying photography planes such as the RB-17 and RB-29, modified recon bombers, before relocation to Barksdale AFB. In 1951 McGuire was reassigned to Air Defense Command, housing a number of pursuit, interception, and other air defense units.

In the later 1950s many of these air defense units were replaced with SAGE radar stations, and McGuire shifted to a data center mission, monitoring for Soviet bomber, and later ICBM, attack. To aid this mission, McGuire was the site of one of the first computers with a magnetic memory, the AN/FSQ-7 Combat Direction Central computer, a 250 ton system covering a half-acre of floor space. It cost $10 billion, had less computing power than a modern cell phone, but was one of the most powerful and versatile computers of the time. This system ran from the late 1950s to the late 1970s, and components of the system were used as a futuristic-looking computer in several movies and TV shows, including Logan's Run, WarGames, and Independence Day, long after it was actually obsolete.

Also in the later 1950s, McGuire adopted an airlift mission, through several command name changes, today Air Mobility Command. McGuire units transport equipment and personnel worldwide; since the end of the Cold War supporting Operations Joint Endeavor, Enduring Freedom, Iraqi Freedom, and Open Arms. Ongoing force reorganization in all armed forces led McGuire to be one of the first bases joined in the 2000s, welding McGuire with Fort Dix and Naval Air Engineering Station Lakehurst into Joint Base McGuire-Dix-Lakehurst in 2009.