Bankhead was a strong liberal and a prominent supporter of President Franklin Roosevelt's New Deal of pro-labor union legislation, thus clashing with most other Southern Democrats in Congress at the time.

His father, John H. Bankhead, was an active politician who had served in the Alabama legislature, and later as US Representative and Senator.

Bankhead served as chairman of the House Rules Committee from April 1934 until January 1935, taking over for Edward W. Pou who died in office.

On June 4, 1936, he was chosen Speaker of the House to succeed Jo Byrns, who had died that morning.

[6] As Speaker, Bankhead held the second-highest political office ever attained by any Alabamian, after only Vice President William R. King.

At the 1940 Democratic National Convention (three months before his death), he finished second to Henry A. Wallace on the vice presidential ticket, losing the delegate count 626–329.

[7] The William B. Bankhead National Forest and sections of old US Highway 78 in northern Alabama are named in his honor.