On 8 December 1940, the nineteen-year-old Isaacson enlisted in the Royal Australian Air Force (RAAF). After completing his training in Australia and Canada, he was posted to the United Kingdom and joined No. 460 Squadron RAAF at RAAF Breighton, Yorkshire, as a sergeant pilot. Operating Vickers Wellington medium bombers, No. 460 Squadron had been raised under the Article XV provisions of the Empire Air Training Scheme and was one of a number of nominally Australian formations taking part in RAF Bomber Command's strategic air campaign against Germany. The squadron commenced operations in March 1942 and participated in 1,000-bomber raids against Cologne, Essen and Bremen in May and June. It converted to Avro Lancaster heavy bombers in October. Isaacson was awarded the Distinguished Flying Medal on 6 November 1942 for "many successful night attacks on the enemy" with No. 460 Squadron. The following month his Lancaster was damaged by a Junkers Ju 88 night fighter after a raid on Munich.