Middleton joined the Army in 1910. Two years later, he was transferred to Fort Leavenworth where he received his commission as an officer. When the U.S. joined the fighting during WW I, 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, his unit led the attack during the Meuse-Argonne Offensive. 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. Although he retired from the Army in 1937, he was recalled to serve during World War II.
During World War II, Middleton led the 45th Infantry Division in its earliest days of battle at Sicily and Salerno. the Sicily and Salerno. In March 1944, he moved up to command the VIII Corps. His leadership in Operation Cobra during the Battle of Normandy led to the capture of the important port city of Brest, France, and for his success he was awarded a second Distinguished Service Medal. His went on lead troops during the Battle of the Bulge, holding the key city of Bastogne, Belgium, and then pushing troops cross Germany until reaching Czechoslovakia. He was recognized by both General Dwight D. Eisenhower, the Supreme Allied Commander, and General Patton as being a corps commander of extraordinary abilities. Middleton logged 480 days in combat during World War II, more than any other American general officer.