After brief training in the United States with Boeing B-17 Flying Fortress aircraft, it was one of the first heavy bomber squadrons to deploy to the European Theater of Operations.

[1][4] The following month, it moved to Sarasota Army Air Field, Florida, where it trained with Boeing B-17 Flying Fortress aircraft and also flew antisubmarine patrols.

[1] The ground echelon sailed on the RMS Queen Elizabeth, arriving in Scotland on 10 June and at RAF Polebrook two days later.

The squadron's B-17s began arriving at Polebrook on 1 July, where they formed part of the first heavy bomber group assigned to Eighth Air Force.

Most pilots had not flown at high altitudes on oxygen; some gunners had never operated a turret, much less fired at a moving target.

The squadron's first weeks in England were devoted to intensive training, with numerous specialists attending Royal Air Force (RAF) schools to prepare for combat.

[4] In September, the 97th Group and its squadrons were transferred to XII Bomber Command in the preparations for Operation Torch, the invasion of North Africa.

[4] The group also flew air support and interdiction missions against enemy lines of communication, airfields and transportation facilities.

Equipped with Boeing B-29 Superfortresses and participated in numerous exercises, operational readiness inspections, and overseas deployments.

The B-50 gave the unit the capability to carry heavy loads of conventional weapons faster and farther as well as being designed for atomic bomb missions if necessary.

Moved to Blytheville Air Force Base, Arkansas and equipped with Boeing B-52G Stratofortress strategic bombers in 1960.

Stood nuclear alert with the B-52G, although deployed aircrew to forward bases in the Western Pacific during the Vietnam War which flew Operation Arc Light and Linebacker I combat missions over Indochina; aircrews participated in the December 1972/January 1973 Linebacker II missions over the Hanoi-Haiphong area of North Vietnam.

On 15 August 1973, after months of committing most of the wing's people and resources to the conflict, crew E-21 had the distinction of flying the last B-52 mission over a target in Cambodia.