Flying from RAF Polebrook in Northamptonshire in early 1943, the group's 504th Bomb Squadron made 54 consecutive missions in June 1943 to January 1944 without losses.

Two members of the 351st Bombardment Group, Second Lieutenant Walter E. Truemper and Staff Sergeant Archibald Mathies, were posthumously awarded the Medal of Honor for a mission to Leipzig, Germany, on 20 February 1944.

Fellow crew member Carl Moore earned the Distinguished Service Cross for his actions during the mission.

In April–May 1943, the unit moved to RAF Polebrook England to serve in combat with Eighth Air Force.

As the war progressed, the 351st operated primarily against strategic objectives in Germany, striking such targets as ball-bearing plants at Schweinfurt, communications at Mayen, marshalling yards at Koblenz, a locomotive and tank factory at Hanover, industries at Berlin, bridges at Cologne, an armaments factory at Mannheim, and oil refineries at Hamburg.

The group also struck harbor facilities, submarine installations, airfields, V-weapon sites, and power plants in France, Belgium, the Netherlands, and Norway.

The 351st Received a Distinguished Unit Citation (DUC) for performance on 9 October 1943, when an aircraft factory in Germany was accurately bombed in spite of heavy flak and pressing enemy interceptors.

The group participated in the intensive air campaign against the German aircraft industry during "Big Week", 20–25 February 1944.

In addition to its strategic missions, the group often operated in support of ground forces and attacked interdictory targets.

During the early years of the Cold War, the 351st Bombardment Group (Very Heavy) was reactivated for a short period between 1947 and 1949 as part of the reserves.

The wing was bestowed the lineage, honors and history of the USAAF 351st Bomb Group of World War II upon activation.