During World War I, the Mayo Clinic continued to be busy. Many draftees were examined and war training classes were conducted for new physicians in the medical corps. William and Charles designed courses to educate military doctors on the latest scientific and surgical developments. The two brothers divided their time between Rochester and their duties in Washington, D.C. so that one of them would always be at the Clinic. This schedule took a toll on their health; Charles contracted pneumonia during one of his stints in Washington, and William developed hepatitis while in Rochester in 1918.
After hostilities ended in November 1918, both of the Mayo brothers were promoted to the rank of Brigadier General (O7) in the U.S. Army Reserve. In addition, they both received the U.S. Distinguished Service Medal for their wartime service to the country.