The 4th was activated at Selfridge Field, Michigan on 15 January 1941 and trained under Third Air Force as a tactical fighter squadron. Moved to several U.S. bases before relocating to Northern Ireland and England in 1942. Equipped with the British Supermarine Spitfire, was assigned to Twelfth Air Force during the North African Campaign in late 1942. Moved across Algeria and Tunisia flying ground support missions for American ground forces; taking part in the invasion of Sicily and Italy in 1943. Participated in the liberation of Corsica in 1943; then returning to Italy and being re-equipped with P-51D Mustangs in May 1944. Participated in Northern Italian Campaign, returning to the United States in August 1945 and inactivating.
Reactivated as part of Thirteenth Air Force in Okinawa, assuming personnel and P-61 Black Widows of the inactivated 418th Night Fighter Squadron. Performed air defense role over Okinawa during Chinese Civil War on the mainland during 1947–1950. Re-equipped with new F-82G Twin Mustangs in 1949, retiring war-weary F-61s in early 1950. Deployed flight of F-82s to Japan in June 1950 as part of Far East Air Force mobility upon breakout of Korean War. Engaged in combat operations over South Korea during 1950, until F-51D Mustangs and F-84 Thunderjets arrived in the Korean theater. Then few combat missions from Japan, rotating flights of F-82s from Okinawa during 1950–1951, largely performing long-range weather reconnaissance flights over North Korea. Began receiving F-94C Starfire jet interceptors to replace F-82s in 1951, retiring the last of its Twin Mustangs in late 1951. Continued air defense mission of Okinawa until 1954; moving to Japan and taking over interceptor mission until 1954 flying first F-86D Sabres then F-102As. Also train pilots of the Japanese Self-Defense Forces, the Republic of Korea and the Royal Thai Air Force, and flew combat missions over Korea and Vietnam.
In June 1965, the 4th moved to Eglin Air Force Base, Florida, and was renamed the 4th Tactical Fighter Squadron, under the aegis of the 33d Tactical Fighter Wing, becoming the fourth Air Force fighter squadron trained in the F-4C Phantom IIs. Deployed in July 1967, to Ubon Royal Thai Air Force Base, Thailand, where they were designated as the 435th Tactical Fighter Squadron and immediately began combat operations. Reassigned in 1969 to Da Nang Air Base, Republic of Vietnam; flying tactical bombing missions over North Vietnam as part of the 366th Tactical Fighter Wing. Remained in Vietnam until United States redeployment from DaNang Air Base in mid-1972. The squadron attained the U.S. Air Force's last Southeast Asia aerial victory, downing a MiG-21 on 8 January 1973. In all the 4th downed four enemy aircraft in combat over Vietnam.
For the next two years, the squadron remained at Udorn Royal Thai Air Force Base, flying cover for evacuations of Phnom Penh, Cambodia and Saigon, Republic of Vietnam. The 4th performed strike missions in support of a recovery operation for the SS Mayaguez, a merchant freighter captured by Cambodian Khmer Rouge guerillas in May 1975.