Harris was born near Tullahoma, Tennessee. He was educated at Winchester Academy in Winchester, Tennessee. He moved to Paris, Tennessee to become a store clerk. He studied law while there and was admitted to the bar in 1841 and began his practice in Paris. He was elected to the Tennessee State Senate in 1847, serving one term there and then two in the U.S. House of Representatives, from 1849 to 1853. During his first term in the House, he chaired the Committee on Invalid Pensions. A Democrat, he was his party's nominee for governor in 1857 and was elected, succeeding Andrew Johnson.

Perhaps rather surprisingly given the troubled and volatile nature of the times, he was re-elected twice, in 1859 and 1861. When President Abraham Lincoln declared that there was rebellion in the South in 1861 and asked for troops to help quell it, Harris refused to make the call, and none were provided. This helped push Tennessee to become the last state to secede from the Union and join the Confederacy.

The Confederate government had lost control of much of Tennessee, including the capital, Nashville, by early 1862. Apparently Harris, upon learning that Lincoln had appointed Andrew Johnson as military governor of Tennessee, Harris, while not resigning formally, ceased to make any real effort to function as governor, serving instead as a staff officer in the Confederate Army, first for Albert Sidney Johnston and then for Joseph E. Johnston.

After the war Harris fled to Mexico and then England. Upon learning that only the highest-ranking officials of the Confederacy were being punished, and that it might be possible for all others to have their civil rights restored, he returned to Tennessee and resumed the practice of law in Memphis, Tennessee. He was subsequently elected to four terms in the U.S. Senate, serving from 1877 until his death, and is, as of 2004, Tennessee's second-longest serving Senator. From 1893 to 1895 (53rd Congress), Harris was president pro tempore of the Senate. Other Senate assignments in his career included chairing the District of Columbia Committee in the 46th Congress and the 53rd Congress, the Committee on Epidemic Diseases in the 49th Congress through the 52nd Congress, and the Committee on Private Land Claims in the 54th and 55th Congresses. His funeral was held in the Senate chamber of the United States Capitol and he is buried at Elmwood Cemetery in Memphis, where many prominent West Tennessee political figures are buried.

This article incorporates facts obtained from the public domain Biographical Directory of the United States Congress.