Recalled to service in early 1942, upon American entry into World War II, Middleton became CG of the 45th Infantry Division during the Sicily and Salerno battles in Italy, and then in March 1944 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 by General George Patton. His greatest World War II achievement, however, was in his decision to hold the important city of Bastogne, Belgium, during the Battle of the Bulge. Following this battle, and his corps' relentless push across Germany until reaching Czechoslovakia, he was recognized by both General Dwight D. Eisenhower, the Supreme Allied Commander, and 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. Retiring from the army again in 1945, Middleton returned to LSU and in 1951 was appointed to the university presidency, a position he held for 11 years, while continuing to serve the army in numerous consultative capacities. He resided in Baton Rouge, Louisiana, until his death in 1976 and was buried in Baton Rouge National Cemetery. Both the Air Force/Army ROTC building at Mississippi State University, Middleton's alma mater, and the library at Louisiana State University are named for him.