Upon the entry of the United States into World War I, in April 1917, Middleton was assigned to the 4th Infantry Division, and soon saw action as a battalion commander during the Second Battle of the Marne. Three months later, following some minor support roles, his unit led the attack during the Meuse-Argonne Offensive, and Middleton became a regimental commander. Because of his exceptional battlefield performance, on 14 October 1918 he was promoted to the rank of colonel, becoming, at the age of 29, the youngest officer of that rank in the American Expeditionary Force (AEF). He also received the Army Distinguished Service Medal for his exemplary service. Following World War I, Middleton served at the U.S. Army School of Infantry, the U.S. Army Command and General Staff School, the U.S. Army War College, and as commandant of cadets at LSU. He retired from the army in 1937 to become dean of administration and later comptroller and acting vice president at LSU. His tenure at LSU was fraught with difficulty, as Middleton became one of the key players in helping the university recover from a major scandal where nearly a million dollars had been embezzled.