Joseph Clay Stiles Blackburn was a member of the State house of representatives from 1871 to 1875. He was then elected as a Democrat to the Forty-fourth and to the four succeeding Congresses (March 4, 1875 – March 3, 1885). He was the chairman of the Committee on the District of Columbia (Forty-fifth Congress) and the Committee on Expenditures in the Department of War (Forty-fifth and Forty-sixth Congresses).

In 1885, Lt. Henry T. Allen of the U.S. army named a mountain after Joseph Blackburn. Mount Blackburn is the highest peak in the Wrangell Mountains of the state of Alaska and the fifth highest peak in the United States.

Blackburn was elected to the United States Senate in 1884, was reelected in 1890, and served from March 4, 1885, to March 3, 1897. He failed to be reelected in 1896. He was the chairman of the Committee on Rules (Fifty-third Congress).

Blackburn was once again elected to the United States Senate in 1900 and served from March 4, 1901 to March 3, 1907, but failed in his next election bid in 1906. Loosely associated with the free-silver wing of the Democratic party, he was well-known nationally and his name was placed in nomination for the presidency in 1896.

Blackburn was appointed Governor of the Panama Canal Zone by President Theodore Roosevelt on April 1, 1907. He resigned in November 1909 and returned to his estate in Woodford County.

He died in Washington, D.C. and was interred in the State Cemetery in Frankfort.