Following the US entry into World War II the 59th Obs Group engaged in antisubmarine patrols along the East coast of the United States from December 1941-October 1943. During 1943 and 1944 the group trained pilots using P-39 aircraft. The 59th was deactivated on 1 May 1944.

During the Korean War, the 3700th Medical Squadron developed a program to train basic trainees as medical corpsmen to ease shortage of medical personnel.

From 1983, Wilford Hall offered centralized outpatient care, a clinical investigation facility, the Air Force's largest dispensary system, and the only eye bank and organ transplant centers. The hospital accomplished important research work in neonatal medicine, surgical transplants, orthopedic surgery, rheumatology, immunology, and maxillofacial surgery. Clinical investigations research kept the wing at the forefront of development of high-frequency ventilation and extra-corporeal membrane oxygenation; new techniques for the care of premature infants; improved cancer treatments; bone banking and transplantation; laser photocoagulation; and acquired immune deficiency syndrome (AIDS). In December 1989, it provided medical support to casualties returning from operations in Panama. From 4 January to 21 March 1991 Wilford Hall deployed over 900 personnel to RAF Little Rissington, England, to establish a 1500-bed hospital in support of expected casualties from the Gulf War.

In 1993 the Medical Center was redesignated the 59th Medical Wing, taking the lineage of the 59th Tactical Fighter Wing.

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