Born in Danville, Virginia and raised in Augusta, Georgia, Lewis attended several colleges, studied law, and attained admission to the bar in 1882.

[1] His mother had traveled to Virginia to nurse his father, who was wounded while serving for the Confederacy in the American Civil War.

[1] In 1896, Lewis received 11 votes for the vice presidential nomination on the first ballot at the Democratic National Convention despite not yet having attained the constitutionally required minimum age of 35.

In 1914, he was the Senate's representative at a London conference that considered way to ensure that laws and treaties guaranteeing safe sea travel could still be implemented as World War I was beginning.

Lewis also performed unspecified special wartime duties in Europe which led to him receiving knighthoods from the kings of Belgium and Greece.

[1] In October 1918, Lewis was aboard an army ship, USS Mount Vernon, when it was hit by German fire.

[6] Upon his defeat for reelection in 1918, Lewis was offered the ambassadorship to Belgium, but he declined and returned to private legal practice in Chicago, Illinois.

He eventually became a partner in the newly named Lewis, Adler, Lederer & Kahn (now known as Saul Ewing Arnstein & Lehr, LLP).

[7] In 1921, 1922, and 1925, Lewis was part of the U.S. delegation to League of Nations conferences held to settle wartime damage claims.

[13] Lewis was known to be something of an eccentric in manner and dress, wearing spats well into the 1930s even though they were out of fashion, and sporting Van Dyke whiskers during an era when most men were clean shaven, as well as a collection of "wavy pink toupees".

[15][16][17] Lewis died at Garfield Hospital in Washington, DC, and his funeral service was held in the Senate Chamber.