After graduation from Yale in 1905 William Lemke set up to law practicing at Fargo. From 1921 to 1922 he served as attorney general of North Dakota. In 1932 Lemke was elected to the United States House of Representatives, where he served four two-year terms. While in Congress, Lemke earned a reputation as a progressive populist and supporter of the New Deal, championing the causes of family farmers and co-sponsoring legislation to protect farmers against foreclosures during the Great Depression.
In 1934, Lemke co-sponsored the Frazier–Lemke Farm Bankruptcy Act, which would have provided refinancing of farm mortgages for government. President Franklin D. Roosevelt refused to support Lemke on that issue and ultimately sank the bill. Later in 1936, Lemke accepted the nomination of the Union Party, a short-lived third party, as their candidate for President of the United States. He received 892,378 votes, or just under 2% nationwide, and no electoral votes. Simultaneously, he was reelected to the House of Representatives as a Republican. Many believe that his acceptance of the Union Party nomination in 1936 was out of bitterness toward Roosevelt over the farm mortgage issue.
In 1940, after having already received the Republican nomination for a fifth House term, Lemke withdrew from that race to launch an unsuccessful run as an independent for the U.S. Senate. He ran again for Congress in 1942 as a Republican and served four more terms, until his death in 1950.