The 53rd TFS dates back from in 1941, when the AAC (U.S. Army Air Corps) activated the 53rd Pursuit Squadron at Albrok Field, but immediately deployed the newly formed Squadron to the Panama Canal Zone. The First Aircraft to arrive, was the P-26 Peashooter, followed shortly by the P-36 Hawk.

In May 1943, the 53rd returned back to the US to be re-equipped with the P-47D Thunderbolt II. A year later in 1944 the squadron moved to Kingsnorth, England to participate in the Landing at Normandy (France). At the end of hostilities in Europe, the Squadron moved to Fürstenfeldbruck in Germany, to form together with the 22 FBW the 36th TFW. Later on, the 36th Moved to Bitburg AB, where they received it's first F-15A/B's in 1977, replacing its F-4E Phantoms. Flying the Eagle’s, the 53rd TFS scored 11 air-to-air kills during the 1991 Gulf War.

In 1994 the Squadron moved its personnel and 18 of its 24 F-15C/D aircraft to Spangdalem AB, Germany, Joining the 52nd Fighter Wing. The 53rd Fighter Squadron was part of the NATO Tiger Association until it's inactivation in 1999.

On 10 December 2021, it was activated as an associate unit to the 113th Wing's 121st Fighter Squadron at JBA. The activation comes as the 53rd FS launches a full partnership with the District of Columbia Air National Guard's 121st FS/113th Wing, as part of the USAF's Total Force Integration initiative, which partners active duty personnel with National Guard units for training and staffing.