Activated on 15 November 1942 at Hamilton Field, California, initially equipped with Bell P-39 Airacobras and assigned to IV Fighter Command for training.

Transitioned to the Mustang throughout the summer of 1943 the deployed to the European Theater of Operations, being assigned to IX Fighter Command in England.

In late 1943, the strategic bombardment campaign over Occupied Europe and Nazi Germany being conducted by VIII Bomber Command was taking heavy losses in aircraft and flight crews as the VIII Fighter Command's Lockheed P-38 Lightnings and Republic P-47 Thunderbolts lacked the range to escort the heavy Boeing B-17 Flying Fortress and Consolidated B-24 Liberator bombers deep into Germany to attack industrial and military targets.

From its base at RAF Boxted, the unit flew long-range strategic escort missions with VIII Bomber Command groups, escorting the heavy bombers to targets such as Frankfurt, Leipzig, Augsburg, and Schweinfurt, engaging Luftwaffe day interceptors frequently, with the P-51s outperforming the German Messerschmitt Bf 109 and Focke-Wulf Fw 190 interceptors, causing heavy losses to the Luftwaffe.

Was relieved from escort duty and was re-equipped with Republic P-47D Thunderbolts, and moved to RAF Lashenden on the southern coast of England.

Flew fighter sweeps over Normandy and along the English Channel coast of France and the Low Countries, April–June 1944, then engaged in heavy tactical bombing of enemy military targets as well as roads, railroads and bridges in the Normandy area to support ground forces in the immediate aftermath of D-Day.

Later, in 1944, the squadron became involved in dive-bombing and strafing missions, striking railroad yards, bridges, troop concentrations, and airfields.

Participated in attacks on German forces in Belgium in the aftermath of the Battle of the Bulge, then moved eastward as part of the Western Allied invasion of Germany.

Equipped with North American F-100 Super Sabre fighters, the squadron participated in exercises, operations, tests, and firepower demonstrations conducted by the Tactical Air Command within the US and abroad.

In 1971, the 612th and 613th Tactical Fighter Squadrons were reassigned back to the 401st TFW from their deployment in South Vietnam as part of the drawdown of USAF forces in Southeast Asia.

On 12 October 1972, the 353rd (commanded by Lt. Col Brown G. Howard III) deployed to Korat Royal Thai Air Force Base, Thailand as part of the 354th Tactical Fighter Wing (Forward), and engaged in combat operations in the Vietnam War.

Immediately began phasing down with the designated BRAC 1990 closure of Myrtle Beach AFB and the pending inactivation of its host Wing.