A farmer prior to his entry into politics, Tillman, a Democrat, emerged during the 1880s as a spokesman for poor rural whites in South Carolina in their conflict against both the ruling white aristocracy and the impoverished Negro population. The rise of Tillman marked the decline of the former Confederate general Wade Hampton (Hampton, Wade) as a political force in the state. Elected governor in 1890, Tillman translated his populist rhetoric into concrete reforms. He shifted the tax burden to the wealthy, improved public education, founded the agricultural college later to be known as Clemson University, and regulated the railroads. He also helped write the state constitution to disfranchise Negroes and circumvent the Fifteenth Amendment with a patchwork of Jim Crow laws (i.e., laws enforcing racial segregation). An unabashed bigot, he considered lynching an acceptable law-enforcement measure.

Elected to the U.S. Senate in 1894, Tillman served until his death, continuing to press for agrarian reform on the national level. He bitterly assailed Pres. Grover Cleveland for his hard-money policy, supporting instead the free-silver program of William Jennings Bryan. In most instances he opposed the administration of Pres. Theodore Roosevelt (Roosevelt, Theodore). In fact, the two became such bitter enemies that at one point the President barred Tillman from the White House. They put aside their differences long enough, however, to collaborate in securing passage of the Hepburn Act (1906), extending the Interstate Commerce Commission's regulatory powers over the railroads. Tillman was floor leader for the bill. He generally supported Pres. Woodrow Wilson and, as chairman of the Senate Naval Affairs Committee, promoted the administration's program to strengthen the Navy. His vituperative and often profane attacks on his political opponents earned him the nickname “Pitchfork Ben”; he once had a fistfight with his South Carolina colleague on the floor of the Senate.