With the outbreak of World War I, Willkie enlisted in the Army as a private, served overseas, and returned home as a captain. After the war, he resumed the practice of law for an industrial corporation in Akron, Ohio, and two years later, he accepted a position with a firm of utility lawyers. During this period, Willkie made several speeches in favor of international cooperation, the improvement of state governmental administration, and opposition to the Ku-Klux Klan.

Willkie was active in the Democratic Party, a delegate to its 1924 convention. While in Akron, Willkie attracted the attention of Bernard C. Cobb, who, in 1929, formed the Commonwealth and Southern Corporation, which was a utility holding company operating in 11 states. Willkie was invited to join the New York legal firm who represented this corporation, and became the new president of the corporation when Cobb retired.

Willkie’s principal activities promptly became the rejuvenation of the electrical industry and assumed the leadership of the utilities’ struggle against governmental competition in the Tennessee Valley. Willkie fought the administration in court, although a Democrat, and soon became recognized as the most articulate critic of Franklin D. Roosevelt’s economic policies.

His economic associations and frequent speeches made him attractive to leaders within the Republican Party, and he ultimately became considered as a nominee for president. Across the country, his supporters began conducting a grassroots campaign and at the Republican Convention Wilkie was swept into the nomination

Throughout autumn of 1940, Willkie waged a vigorous campaign against Roosevelt’s economic policies, aiming his appeal at Democrats and independent voters. He pledged a more unified and prosperous America and an end to unemployment. However, because Willkie agreed with many of the New Deal social reforms and the president’s attitudes on foreign policies, he did not present a clear alternative to the people.

By November, Democratic leaders agreed that Willkie had been the strongest candidate that the Republicans could have nominated, but at the polls the votes remained divided along economic lines. Many voters, concerned with the international situation, cast their ballot with the incumbent. Wilkie lost the election by nearly five million votes.

After the election, Willkie advocated a policy of "loyal opposition" where there would be support for the president in areas crucial to national defense but with partisan criticism in the other fields. He attempted to maintain his Republican Party leadership while supporting the administrations program of assisting the Allies. However, a result of his opposition to isolationists was his lost support in the Republican Party.

As the President’s personal envoy, he made a trip around the world and later wrote One World in 1943, which became a bestselling book. It was a declaration of the need for understanding and cooperation among the people and leaders of al nations. Willkie led the Republican Party to take a stand on supporting membership in a postwar organization, however, many party leaders were alienated with Willkie that he lost control of the organization. When he ran for the presidential nomination in 1944, he was defeated in the Wisconsin primary election, and withdrew from the race.