In August 1940 he was appointed chief of staff of the North Caucasus, from January 1941 to the position of commander of the Central Asian Military District.

With the onset of the Great Patriotic War, he went on to command the district, and at the same time, from August to October 1941, the 53rd Army, which took part, with Soviet forces from the Transcaucasus, in the Anglo-Soviet invasion of Iran.

After Romania switched sides on 23 August 1944, the army under the command of General Trofimenko advanced rapidly into Romania, for the first nine days of fighting passed about three hundred kilometers, while cutting apart the rear of the German-Romanian Army Group "South Ukraine"; this move took possession of the cities of Adjud, Focșani, Buzău, and Ploiești.

General Trofimenko is thought to be responsible for the great loss of Romanian soldiers, whom he later had in command, during the battle of Oarba de Mureș, in Romania.

4262 of the Presidium of the Supreme Soviet of September 13, 1944, for good command of troops in Iași-Kishinev operation and for displaying courage and heroism, Lieutenant-General Sergei G. Trofimenko was awarded the title Hero of the Soviet Union with the award of the Order of Lenin and medal "Gold Star" .