Constituted as 376th Bombardment Group (Heavy) on 19 Oct 1942 and activated in Palestine on 31 Oct. Began combat immediately, using B-24 aircraft. Operated with Ninth AF from bases in the Middle East, Nov 1942-Sep 1943, and with Twelfth AF from Tunisia, Sep-Nov 1943. Attacked shipping in the Mediterranean and harbor installations in Libya, Tunisia, Sicily, and Italy to cut enemy supply lines to Africa. Struck airdromes, marshalling yards, and other objectives in Sicily and Italy after the fall of Tunisia in May 1943. Received a DUC for action against the enemy in the Middle East, North Africa, and Sicily, Nov 1942-Aug 1943. Participated in the famed low-level assault on oil refineries at Ploesti and received another DUC: nearing Ploesti on 1 Aug 1943 and realizing that it was off course, the group attempted to reach its assigned objective from another direction; by this time, however, enemy defenses were thoroughly alerted and intense opposition forced the 376th to divert to targets of opportunity in the general target area

Moved to Italy in Nov 1943 and operated with Fifteenth AF until Apr 1945. Engaged primarily in long-range missions to targets in Italy, France, Germany, Czechoslovakia, Austria, Hungary, and the Balkans to bomb factories, marshalling yards, oil refineries, oil storage facilities, airdromes, bridges, harbors, and other objectives. Received a DUC for attacking the oil industry at Bratislava on 16 Jun 1944. Also flew support and interdictory missions, assisting Allied forces at Anzio and Cassino during Feb-Mar 1944, supporting the invasion of Southern France in Aug 1944, aiding the Russian sweep into the Balkans during the fall of 1944, and assisting Allied troops in northern Italy during Apr 1945.

Moved to the US in Apr. Redesignated 376th Bombardment Group (Very Heavy) in May 1945. Inactivated on 10 Nov 1945.