Seymour Johnson AFB was established in April of 1942 as Headquarters, Technical Training School, Army Air Corps; training Field Aviation Cadets in pre-technical training for eventual bomber mechanic occupation leadership.

Seymour Johnson was a Navy test pilot from the Goldsboro area who had been killed in service shortly before the base opened.

In June 1943 a new mission was added, preparing officers and enlisted personnel for overseas duty. In September 1943 a new training wing was established to pre-train Aviation Cadets intended for technical duties. In October 1943 Seymour Johnson gained the 326th Fighter Group, which began training P-47 Thunderbolts in early 1944; this became the primary mission of Seymour Johnson Field in April 1944. At the end of the war Seymour Johnson was engaged in training bomber crews for night missions over Japan, and general assembly and training point for troops being redeployed from Europe to the Pacific, when the end of the war cut these missions short. Seymour Johnson became a service separation center, and activity at the base wound down until it was deactivated and closed in 1946, coming under control of the city of Goldsboro.

From 1946 to 1952 the field was used for civilian and commercial aviation, and in 1952 was transferred from the city to Federal control. The US Army Corps of Engineers demolished the old base buildings and constructed new ones. In 1956 the base was reopened as a US Air Force Base, and assigned a fighter wing. This wing was replaced a year later by the 4th Fighter Wing as host unit, which remains the host unit to modern times.

The 4th Fighter Wing traces its history to World War Two, when it was activated from pilots and personnel from the Eagle Squadron American volunteers in the United Kingdom's Royal Air Force; when the US entered the war, these volunteers transferred to US Air Corps service, forming the 4th Fighter Group, later expanded to wing. The 4th Fighter Wing has a distinguished history as a fighter-interceptor unit, tactical fighter unit, night strike, and precision strike unit, from the Korean War to the Global War on Terror. In recent years the 4th has flown the F-15 Strike Eagle, as it did in Operation Desert Storm, providing outstanding service, mainly in night missions.

In the Cuban Missile Crisis of 1962 the 482nd Fighter Interceptor Squadron, stationed at Seymour Johnson, was one of the first units deployed to quarantine Cuba and prevent the delivery of Soviet nuclear warheads.

Seymour Johnson also hosted a strategic bomber wing, the 68th, from 1958 to 1982, when the bomber mission was replaced with an air refueling mission, which continued to the mid-1990s, when the relocation of the 68th and its absorption into other units as part of the post-Cold War reorganization. Some of the air refueling mission is today partly absorbed as the mission of other Seymour Johnson units.

Today, Seymour Johnson continues as a stable air defense base, and has recently been housing units from other realigned bases.