Born in Norfolk Virginia, he moved to North Carolina before age 2. After graduating from Trinity College (now the undergraduate liberal arts college of Duke University) in 1910 and Duke University Law School in 1912, he became a practicing attorney—but interrupted his work to serve in the United States Army during World War I. In 1912, he founded the law firm that eventually became known as Smith, Anderson, Blount, Dorsett, Mitchell & Jernigan (informally "Smith Anderson").^[1]

Smith served in the North Carolina House of Representatives from 1927 to 1932, and was briefly the speaker of that body in 1931.^[2] He also served as a U.S. observer at the Nuremberg Trials in 1946, as chairman of the American delegation to the Inter-Parliamentary Union in Bern, Switzerland in 1952, as chairman of the Duke University board of trustees (1947 - 1953), and as president of the American Bar Association (1945-1946).^[3]

In the Democratic primary of 1950, Smith defeated incumbent Sen. Frank Porter Graham for the nomination. Graham had been appointed to fill the vacancy caused by the death of J. Melville Broughton and had served only a little over a year at the time of his defeat. In a campaign distinguished by race-baiting,^[4] Graham, who was well known for his civil rights sympathies, was supported by President Harry Truman and the state's liberal Democratic faction, while Smith was aided by strategist Jesse Helms.

Smith's service in the Senate was brief and unremarkable.^{[according to whom?]}

He died due to coronary thrombosis in 1953 in Bethesda, Maryland^[5] and was interred at the Historic Oakwood Cemetery in Raleigh, North Carolina.

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  Campaign flyer for Willis Smith for Senate in the 1950 US Senate race in North Carolina.

• List of United States Congress members who died in office (1950–99)