The unit controlled numerous miscellaneous Air Service light observation squadrons to protect the Panama Canal area.

Throughout the 1920s and 1930, the group participated in manoeuvres, flying patrol missions, photographing the canal area, staging aerial reviews and making good-will flights to Central and South America.

In 1933, the group became part of the larger 19th Composite Wing, which provided a central command and control organization for the Air Service units.

Communications were also being stressed, as qualified radio operators were in short supply, while the squadrons rotated in and out of Rio Hato Army Air Base on "live" bombing practice.

In 1941 it was assigned to the new VI Bomber Command[3] of Sixth Air Force with an antisubmarine mission on both the Caribbean and Pacific approaches to the Panama Canal.

Rusbridger suggested that a collision reported by the American freighter Thompson Lykes on the night of 18 February, sustained damaged to the submarine's radio antenna with the stricken vessel limping towards Panama.

The 6th then began engaging in very long range bombardment missions over the Japanese Home Islands, striking Tokyo and other major Japanese cities and facilities during daylight high-altitude bombing raids, with crippling, non-stop incendiary raids which destroyed lines of communication, supply, and numerous kamikaze bases.

On 25 May 1945, the 6th flew a low-altitude night mission through alerted enemy defenses to drop incendiary bombs on Tokyo, for which they received their first Distinguished Unit Citation.

By mining harbors in Japan and Korea in July 1945, the group contributed to the blockade of the Japanese Empire earning their second Distinguished Unit Citation.

The 6th's final World War II mission came on 14 August 1945, with the dropping of 500-pound general-purpose bombs on the Marifu railroad yards at Iwakuni.

It was inactivated in June 1952 as part of the implementation of the postwar Tri-Deputate organization, as all operational flying squadrons were assigned directly to the 6th Bombardment Wing.