The planes were housed in a corrugated sheet metal hangar erected on the field during the National Air Races in 1923 and later turned over to the squadron.

Their chief pilot on the "St. Louis to Chicago" airmail run was a young man named Charles Lindbergh.

Lindbergh became a member of the 110th as a 2nd lieutenant on 14 March 1925 and held the rank of captain when he made his historic 1927 Trans-Atlantic solo flight.

The Guardsmen were ordered into active service on 23 December 1940 as part of the buildup of the Army Air Corps after the Fall of France.

In early 1943, it was assigned to Third Air Force and trained as a combat reconnaissance unit, being equipped with a mixture of photo-recon A-20 Havocs and B-25 Mitchells.

Reinforced with armed P-40 and P-39 fighters, it also flew combat mission against Japanese installations, airfields, and shipping, while supporting Allied ground forces on New Guinea and Biak.

At Berstrom, its mission was as a filler replacement for the 27th Fighter-Escort Group which was deployed to Japan as part of SAC's commitment to the Korean War.

The unit was at Bergstrom until November when it was transferred to Tactical Air Command (TAC) and moved to George AFB, California.

At George, the unit was scheduled to be re-equipped with F-84D Thunderjets and was programmed for deployment to Japan, however, the F-84s were instead sent to France and the 131st Fighter-Bomber Wing remained in California and flew its F-51 Mustangs for the remainder of its federal service.

Shortly after its return to Lambert Field, the 110th was reformed as a light bombardment squadron in January 1953 and was moved under Tactical Air Command.

It received B-26 Invaders that returned from the Korean War and trained primarily in night bombardment missions, which the aircraft specialized in while in Korea.

While in France, the Guardsmen assumed regular commitments on a training basis with the U.S. 7th Army as well as maintaining a 24-hour alert status.

In 1978, the unit acquired the "home grown" McDonnell Douglas F-4C Phantom II, the aircraft primarily being piloted by Vietnam War veterans.

Between June and July 1982, the 110th TFS deployed twelve Phantoms to RAF Leeming in the United Kingdom to participate in Exercise Coronet Cactus.

More than 500 members from the 131st Fighter Wing and the tenant units located at Lambert International Airport were called into service to battle the Great Flood of 1993.

In the post-Cold War era, the unit deployed to Incirlik AB, Turkey in support of Operation Northern Watch in 1996, 1997 and 1998.

Eventually, a total of about 430 wing members were scheduled to deploy, with the majority leaving in October 2000 for Prince Sultan AB, Saudi Arabia, in support of Operation Southern Watch.

On 30 May 2007, a 110th FS F-15D pilot ejected safely from his aircraft (78-0571) just before it crashed during a training mission in rural Knox county, Indiana.

The plane went down just before 11 am EDT south of Vincennes, near the Illinois border, as it conducted standard training maneuvers, according to a release from the National Guard.

The crash was due to a flaw in a part of the plane's fuselage; this led to all F-15 aircraft being grounded at one point between November and January 2008.

The ceremony celebrated the first official drill for traditional guardsmen at Whiteman and the grand opening of building 3006, the 131st Bomb Wing's first headquarters there.

In March 2011, crew from the 110th BS participated in Operation Odyssey Dawn, which saw airstrikes over Libya against the forces of Muammar Gaddafi.

In March 2020, the squadron deployed to RAF Fairford, UK, alongside the 509th Bomb Wing as part of a Bomber Task Force.