The squadron concentrated on striking strategic targets, concentrating on airfields, oil facilities and rail transportation hubs. From 20 to 25 February 1944, it participated in the Big Week attacks on the German aircraft industry. It was occasionally diverted to attack tactical targets. In preparation for Operation Overlord, the invasion of Normandy, it participated in Operation Crossbow, attacks on V Weapons sites and also bombed transportation targets near the beaches. It continued these attacks and attacked coastal defenses during the month of June 1944. It supported Operation Cobra, the breakout at Saint Lo, and operations in the Battle for Caen. In September it airdropped supplies to airborne forces engaged in Operation Market Garden, the attempt to establish a bridgehead across the Rhine in the Netherlands. It also flew missions to check enemy advances during the Battle of the Bulge by striking communications and transportation targets. The 506th flew resupply missions during Operation Varsity airborne assault across the Rhine. The squadron flew its last combat mission on 25 April 1945.