Philip La Follette and the new Wisconsin Progressive Party, which split from the Republicans in 1934, won the election.

In 1944, Wiley was challenged by United States Marine Corps Captain Joseph R. McCarthy in the Republican primary.

Wiley, then an isolationist in foreign policy, and Governor Walter S. Goodland supported Republican presidential nominee Thomas E. Dewey in the 1944 race over incumbent Franklin D. Roosevelt, and Dewey won Wisconsin's electoral votes but fell short nationally.

[5] In 1962, Wiley lost his bid for a fifth term to Governor Gaylord Nelson, a liberal Democrat.

Wiley had a distinguished Senate career that included the chairmanship of both the Foreign Relations and Judiciary committees.