Borah was born on a farm near Fairfield, Illinois. His schooling included the Wayne County common schools and the Southern Illinois Academy at Enfield. Graduating from the University of Kansas at Lawrence in 1889, he studied law and was admitted to the bar in September 1890. After practicing law in Lyons, Kansas, he relocated to Boise, Idaho in 1890, where he became the most prominent attorney in the state. In 1907, shortly after entering the Senate, Borah was pitted against Clarence Darrow as the prosecuting attorney in the nationally publicized trial of "Big Bill" Haywood and two other radical labor union officials for the 1905 murder of former Idaho Governor Frank Steunenberg.

In 1906, the Idaho Legislature elected Borah to the U.S. Senate over the controversial Democratic incumbent, Fred Dubois. Borah was reelected by the Idaho Legislature in 1912, and four more times by popular vote (1918, 1924, 1930 and 1936). He remains the longest-serving United States Senator in Idaho history.

A member of the Republican National Committee from 1908 to 1912, he was a delegate to the 1912 Republican National Convention. As a Senator he was dedicated to principles rather than party loyalty, a trait which earned him the nickname "the Great Opposer." He disliked entangling alliances in foreign policy and became a prominent anti-imperialist and nationalist, favouring a continued separation of American liberal and European Great Power politics. He encouraged the formation of a series of world economic conferences and favored a low tariff.

In 1919 Borah and other Senate Republicans, notably Henry Cabot Lodge of Massachusetts and Hiram W. Johnson of California, clashed with President Woodrow Wilson over Senate ratification of the Treaty of Versailles ending World War I and establishing the League of Nations. Borah emerged as leader of the "Irreconcilables," a group of senators noted for their uncompromising opposition to the treaty and the League. During 1919 Borah and Johnson toured the country speaking against the treaty in response to Wilson's own speaking tour supporting it. Borah's empassioned November 19, 1919, speech on the Senate floor in opposition to the treaty and League of Nations was considered to be instrumental in the Senate's ultimate rejection of it .

From 1925 to 1933, Borah served as the Chairman of the Senate Foreign Relations Committee. As Chairman, he became known for his pro-Soviet views, favoring recognition of the Communist regime, and sometimes interceded with that government in an unofficial capacity during the period when Moscow had no official relations with the United States. Purportedly, Kremlin officials held Borah in such high esteem that American citizens could gain permission to travel throughout the Soviet Union with nothing more than a letter from the Senator.

Domestically, he sponsored bills that created the Department of Labor and the Children's Bureau. He was one of the Senators responsible for uncovering the scandals of the Harding Administration. Borah supported Roosevelt's New Deal, especially old-age pensions and the reduced gold content of the dollar.

Borah conducted a long-time affair with Alice Longworth, the daughter of Theodore Roosevelt and the wife of fellow politician Nicholas Longworth. He was long rumored to be the biological father of Alice Longworth's only child, Paulina Longworth, who was born nearly 20 years into her parents' marriage.

Known for his integrity, eloquent speaking ability, and genuine concern for his constituents, William E. Borah died in Washington, D.C., on January 19, 1940 of a cerebral hemorrhage at the age of 74. He is buried in Morris Hill Cemetery in Boise.

In 1947, the state of Idaho donated a bronze statue of Borah to the National Statuary Hall Collection. Idaho's highest point, Borah Peak, at 12,662 feet, is named for Borah. Two public schools in the state bear his name: Borah High School in Boise, and Borah Elementary School in Coeur d'Alene, as well as an annual symposium on foreign affairs at the University of Idaho in Moscow. In addition, a residence hall and a theater in the student union building are named for the senator.

Preceded by: Fred Dubois U.S. Senator (Class 2) from Idaho March 4, 1907-January 19, 1940 Served alongside: Weldon B. Heyburn, Kirtland I. Perky, James H. Brady, John F. Nugent, Frank R. Gooding, John W. Thomas, James P. Pope, D. Worth Clark Succeeded by: John W. Thomas Preceded by: Pre-17th Amendment Republican Party nominee, U.S. Senator (Class 2) from Idaho 1918 (won), 1924 (won), 1930 (won), 1936 (won) Succeeded by: John W. Thomas