The 385th BG operated primarily as a strategic bombardment organization until the war ended, striking such targets as industrial areas, air bases, oil refineries, and communications centres in Germany, France, Poland, Belgium, the Netherlands and Norway.

The group received a Distinguished Unit Citation for bombing an aircraft factory at Regensburg on 17 August 1943 after a long hazardous flight over enemy territory.

The group led the 4th Bomb Wing a great distance through heavy and damaging opposition for the successful bombardment of an aircraft repair plant at Zwickau on 12 May 1944, being awarded another DUC for this performance.

Other strategic targets included aircraft factories in Oschersleben and Marienburg, battery works in Stuttgart, airfields in Beauvais and Chartres, oil refineries in Ludwigshafen and Merseburg, and marshalling yards in Munich and Oranienburg.

On 6 March 1944 raid to Berlin (the most costly mission the Eighth ever carried out) the 3rd Division commander, Brigadier General Russell Wilson, took off from Great Ashfield in a radar-equipped B-17 in a leading group of the 385th.

Although four of the crew managed to parachute to safety (including Medal of Honor hero First Lieutenant John C. Morgan), eight of the others were killed when the bomber exploded.