The squadron served in the Panama Canal Zone during the Inter-War period, then as part of the Twentieth Air Force in the Pacific Theater of Operations of World War II flying Boeing B-29 Superfortress bombers.

During the Cold War, it was part of Strategic Air Command, equipped with Boeing B-47 Stratojet medium bombers[3] until its inactivation in 1964.

[7] The 25th has deployed equipment and personnel to support combatant commander operations and large force exercises such as Austere Challenge.

[2] After the United States' entry into World War I, the squadron deployed to Europe aboard RMS Carmania, first to England, then to the Western Front in France in late October 1918. it was assigned to the 4th Pursuit Group of the Second Army Air Service in the Toul Sector, but without any airplanes.

The squadron finally received some British Royal Aircraft Factory S.E.5s, mostly armed with a single fuselage-mounted Vickers machine gun, and flew two missions in November 1918 days before the war ended.

Although eventually found to have made an emergency forced landing in Ecuador, three B-18s of the squadron conducted extensive searches of the area along the 80th meridian some 250 miles to sea.

After the attack on Pearl Harbor, the squadron left its long time home at France Field for Rio Hato Airport, Panama.

The main body of the Squadron left Salinas by 15 February and returned to Howard Field in early 1943, although a detachment was still in Ecuador as late as 30 June.

It deployed with the new XX Bomber Command as part of the 58th Bombardment Wing to the China-Burma-India Theater, flying to bases in India via South Atlantic ferrying route; across central Africa and Arabia to Karachi.

[11] It performed a total of nine missions to Japan, also engaged in very long range attacks against enemy targets in Thailand, Manchuria, Borneo, Formosa, Burma, Malaya, Japanese-occupied China, Singapore, Saigon and Cam Rahn Bay, French Indochina.

[11] The advance of American forces in the Central Pacific though the Northern Mariana Islands made new airfields available within the effective bombing range of Japan.

From the Marianas, it engaged in very long range strategic attacks on Japan, its first mission being on 5 May 1945 against the Hiro Naval Aircraft Factory in Kure.

[11] After V-J Day, the squadron dropped food and supplies to Allied prisoners in Japan, Korea, and Formosa, and took part in show-of-force missions.

The propeller-driven B-29s were replaced with new Boeing B-47E Stratojet swept-wing medium bombers in 1954, capable of flying at high subsonic speeds and primarily designed for penetrating the airspace of the Soviet Union.