Upon activation, the 180th TFG was assigned to the Ohio ANG 121st Tactical Fighter Wing at Lockbourne Air Force Base.

Individual squadron members volunteered for duty during the Vietnam War, however the unit was not federalized in 1968 as the F-84F Thunderjets flown by the 112th TFS were not considered front line combat aircraft.

In 1971, the squadron retired its Thunderstreaks and converted to the F-100 Super Sabre as a result of the American draw-down from the Vietnam War.

In 1975, the 112th began a NATO commitment, deploying five F-100s to Ramstein Air Base, West Germany 9–25 October 1975 for Operation Coronet Razor.

It came from the 312th Tactical Fighter Training Squadron at Luke AFB, Arizona on the rare leap year date 29 February 1992.

Many of the block 25s that came from the 363d Tactical Fighter Wing at Shaw AFB, South Carolina were Desert Storm veterans.

In October 1996, the 112th Expeditionary Fighter Squadron (112 EFS) was first formed from 162d FW personnel and eight aircraft and deployed to Incirlik Air Base, Turkey.

In January 1997, this changed to Operation Northern Watch just prior to the unit's return to Toledo to enforce the No-Fly-Zones over Iraq.

The F-16 aircraft currently assigned to the 132d Fighter Wing at Des Moines would be redistributed to the 180th Fighter Wing (nine aircraft) Des Moines' F-16s would be distributed to Toledo to support the Homeland Defense Air Sovereignty Alert (ASA) mission and to consolidate the precision-guided weapon employment capability that exists in the Air National Guard.

In August 2008 the 112th FS took over the alert role for the region from the Detroit-based Michigan 107th Fighter Squadron which was converting to the A-10 Thunderbolt II in the next year.