The squadron assembled at its combat station, RAF Great Ashfield, England, and began participating in the strategic bombing campaign against Germany, flying its first combat mission on 17 July 1943. The unit carried out attacks on industrial targets, including communications centers as well as air bases in Belgium, France, Germany, the Netherlands, Belgium and Norway, striking targets as far away as Poland. On 17 August 1943, the squadron participated in an attack on the Messerschmitt aircraft factory at Regensburg, which involved a long flight over heavily defended enemy territory with little protection from escorting fighters. For this mission, the squadron received the Distinguished Unit Citation. On 12 May 1944, the squadron flew with the 385th Group as it led the 4th Combat Bombardment Wing through heavy opposition to attack an airplane repair facility at Zwickau. An estimated 200 enemy fighters attacked the bomber stream, heavily disordering its formation. The bombers were able to reform and achieved a high degree of accuracy with their bombs. For this attack, the 549th received a second DUC.