With the United States' entry into World War II, the 122nd returned to New Orleans in December 1941 to conduct anti-submarine patrol over the Gulf of Mexico.

Several months later the A-20s were replaced by Lockheed P-38 Lightnings, Bell P-39 Airacobras and Curtiss P-40 Warhawks, and the unit was reorganized as a branch of the North African Fighter Training Command.

In the summer of 1943, the unit was moved to Bertaux, Algeria, where members trained French and American pilots in navigation and general fighting tactics.

Equipped with highly modified Boeing B-17 Flying Fortresses and Consolidated B-24 Liberators, the unit transported supplies to partisans and engaged in nighttime special operations missions, flying into Occupied France, Fascist Italy, Yugoslavia and other parts of Occupied Europe supporting partisans and parachuting Allied Agents into enemy territory.

Parts were no problem and many of the maintenance personnel were World War II veterans so readiness was quite high and the planes were often much better maintained than their USAF counterparts.

With the surprise invasion of South Korea on 25 June 1950, and the regular military's complete lack of readiness, the ANG was mobilized into federal active duty.

Following the end of the Korean War, the B-26s began to be withdrawn from active service and replaced by jet-powered equipment such as the Martin B-57 Canberra and the Douglas B-66 Destroyer.

The 122nd was re-equipped with former active-duty B-26s and continued training with the versatile light bomber under the Texas Air National Guard's 136th Fighter-Bomber Wing, being operationally gained by TAC.

The B-26s were sent to storage at Davis-Monthan Air Force Base, Arizona (many would be later used in the Vietnam War as counter-insurgency aircraft), and the 122nd was redesignated as a Fighter-Interceptor Squadron on 1 June 1957.

With the F-86L, the squadron was selected by ADC to man a runway alert program on full 24-hour basis – with armed jet fighters ready to "scramble" at a moment's notice.

In the early 1990s, squadron aircraft and personnel were deployed to Aviano Air Base, Italy, flying combat missions over the former Yugoslavia during the Kosovo War as part of Operation Allied Force.

In response to the 9/11 attacks in 2001, the 122nd Fighter Squadron engaged in Combat Air Patrols over major United States Cities as part of Operation Noble Eagle (ONE).

[citation needed] The most recent deployment of the 122nd Expeditionary Fighter Squadron was completed in October 2012 when the squadron deployed to at Al Dhafra Air Base, United Arab Emirates, and as part of the 380th Expeditionary Operations Group, the 122nd EFS flew missions in support of the joint air defense of the Persian Gulf and Operation Enduring Freedom.

The mission included providing air superiority in support of national military objectives and flying fighter integration sorties with F-22 Raptors and McDonnell Douglas F-15E Strike Eagles.