After the beginning of German invasion in June 1941, Yepishev became responsible for directing the war effort in the region: he mobilized the Kharkov people's militia, of which he was the commissar, and organized partisan formations. In October 1941, shortly before the city's fall to the enemy, he was evacuated to the Urals, where he was appointed first secretary of the Party committee in Nizhny Tagil, and as such was responsible for the rebuilding of the arms factories transferred from the front line areas. In November 1942, he became the CPSU Central Committee's commissioner for personnel matters. On 22 December 1942 he was also appointed Deputy People's Commissar for medium machine building. During the Battle of Stalingrad, he was briefly stationed in the Stalingrad Front's military council. In February 1943, he was removed of all his posts and re-instated as the Kharkov party chief, as the Red Army seemed to recapture the area. On 26 May, Yepishev was given the rank of a major general and posted as member of the military council, the highest political officer, in General Kirill Moskalenko 40th Army. As such, he participated in the Battle of Kursk and the Lower Dnieper Offensive. On 2 November, he received the same position in the 38th Army, again under Moskalenko, and held it until the end of the Second World War. The 38th took part in the Battle of Kiev, the Dnieper–Carpathian Offensive, the Lvov–Sandomierz Offensive, the Battle of the Dukla Pass and the Prague Offensive.