Began combat with Fifteenth Air Force in February 1944, operating chiefly against strategic targets until late in April 1945.

Early operations included attacks against such objectives as marshalling yards, aircraft factories, railroad bridges, and airdromes in Italy, Austria, and Romania.

Received a Distinguished Unit Citation for performance at Wiener Neustadt, Austria on 10 May 1944: when other groups turned back because of adverse weather, the 456th proceeded to the target and, withstanding repeated attacks by enemy interceptors, bombed the manufacturing center.

At the same time, expanded previous operations to include attacks on oil refineries and storage facilities, locomotive works, and viaducts in France, Germany, Czechoslovakia, Hungary, Austria, and the Balkans.

Received second DUC for a mission in Hungary on 2 July 1944 when the group braved severe fighter attacks and antiaircraft fire to bomb oil facilities at Budapest.

In April 1945 bombed gun positions, bridges, roads, depots, and rail lines to support US Fifth and British Eighth Army in their advance through Italy.

Its members earned two Presidential Unit Citations for valor in combat and participated extensively in the strategic bombing campaign against oil production targets including Ploieşti, Romania, that resulted in high bomber losses.

On 30 July 1943, the group's ground echelon moved to Bruning Army Air Field, Nebraska, where it remained until 8 October.

By 1 November, to train approximately 70 crews, the 456th had received only 28 aircraft, all old and half of them grounded for maintenance or lack of spare parts.

Despite the group's lack of preparation, and the refusal by Colonel Steed to certify its combat readiness to POM inspectors, the 456th's air echelon was ordered to discontinue training.

The ground campaign in Italy had captured Foggia and its network of potential airfields, and seven groups of Liberators originally slated for the Eighth Air Force, including the 456th, had been diverted by General Arnold to the new bases then under construction.

Traveling individually between December and February, the aircraft flew to Italy using the South Atlantic Ferry Route, established by Pan American Airways in the 1930s: Palm Beach, Florida; Puerto Rico; Trinidad; Belém and Natal, Brazil; Dakar, French West Africa; Marrakech and Casablanca, French Morocco; Oran, Algeria; and Tunis, Tunisia, where it waited while construction was completed on its airfield.

On 23 January, the ground echelon traveled by open truck in wet, freezing weather to the new base (code-named "Newbox") on the Tavoliere near the Adriatic Sea, eighteen miles (29 km) southeast of Foggia.

Staff officers immediately began requisitioning farmhouses for administrative buildings and setting up tent encampments in nearby olive groves for the living quarters.

On a training familiarization flight on 6 February another B-24 was lost, crashing into a mountain while flying in clouds, killing all aboard including three aircraft commanders.

The original group identification aircraft markings for the 456th Bomb Group, located on the outward side of the B-24's twin tail fins, consisted of a black diamond symbol superimposed on a white circle (marking of the 304th Bombardment Wing) on the fin's upper half, and the number 3 in white on the lower half.

In May 1944, with the numbers of olive drab aircraft diminishing rapidly by combat attrition and operational wear, the Fifteenth Air Force adopted a system of color bands and symbols.

The 456th was tasked to attack a German command post near Grottaferrata and encountered no opposition, but when the group reached the target area, they found it completely obscured by clouds and returned without dropping their bombs.

Although judging the results of bombing as successful, the 456th was engaged by nine fighters and severe flak, suffering its first combat losses as two bombers were shot down.

The 456th made the first of ten attacks on Ploieşti oil facilities on 5 May 1944, losing three aircraft, including one when a crewman bailing out of a stricken bomber knocked part of the wing off another in the same formation.

The second box of the 456th bore the brunt of the attacks, with the 744th Bomb Squadron losing six of nine bombers in the target area and a seventh damaged beyond repair.

Beginning 8 July, the first crews of the 456th completing the 50 missions required for a combat tour by the Fifteenth Air Force began returning to the United States.

Bombing of German lines of communication, particularly marshalling yards and railroad bridges, remained a priority to the end of the war.

The following day, while General of the Army Henry H. Arnold, commanding general of the USAAF, was visiting the base, the 456th flew its last mission of the war against a transportation depot at Tarvisio, Italy, and scored a bombing accuracy of 100%, matched by only one other group in Europe (the 467th Bomb Group, also a B-24 unit, of the Eighth Air Force had accomplished it on 13 April 1945).

The 456th relocated to Smoky Hill Army Air Field, Kansas, on 17 August 1945, for conversion to the Boeing B-29 Superfortress and operations against Japan, and was redesignated as the 456th Bombardment Group, Very Heavy.