Isham Green Harris was born in Franklin County, Tennessee, the ninth child of Isham Green Harris, a slave-holding farmer and Methodist minister, and his wife Lucy Davidson Harris.
His parents had moved from North Carolina to Middle Tennessee in 1806. He was educated at Carrick Academy in Winchester, Tennessee, until he was fourteen. He moved to Paris, Tennessee, where he joined up with his brother William, an attorney, and became a store clerk. In 1838, with funds provided by his brother, Harris established his own business in Ripley, Mississippi, an area that had only been recently opened to settlers after a treaty with the Chickasaw Indians. While in Ripley, Harris studied law. He sold his successful business three years later for $7,000 and returned to Paris where he continued studying law under Judge Andrew McCampbell.
Harris was 43 years old when the Civil War began; he was governor of Tennessee.
On May 3, 1841, he was admitted to the bar in Henry County and began a lucrative practice in Paris. He was considered one of the leading criminal attorneys in the state.
On July 6, 1843, Harris married Martha Mariah Travis (nicknamed "Crockett"), the daughter of Major Edward Travis, a War of 1812 veteran. The couple had seven sons. By 1850 the family had a 300-acre (120 ha) farm and a home in Paris. By 1860 their total property was worth $45,000 and included twenty slaves and a plantation in Shelby County.
Harris rose to prominence in state politics in the late 1840s when he campaigned against the anti-slavery initiatives of northern Whigs.
He was elected governor amidst rising sectional strife in the late 1850s, and following the election of Abraham Lincoln in 1860, persistently sought to sever the state's ties with the Union.
In 1857, Tennessee's Democratic governor, Andrew Johnson, was seriously injured in a train accident, and was unable to run for reelection. Harris was nominated as his replacement, and embarked on a campaign that included a series of debates with his opponent, Robert H. Hatton. With sectional strife in Congress fueling both campaigns, these debates were often heated, and fights frequently broke out among spectators (and in one instance, between Harris and Hatton). Hatton was unable to distance himself from northern abolitionists, and Harris won the election by a vote of 71,178 to 59,807.
He served as Governor of Tennessee from 1857 to 1862. He was the state's first governor from West Tennessee. A pivotal figure in the state's history, Harris was considered by his contemporaries the person most responsible for leading Tennessee out of the Union and aligning it with the Confederacy during the Civil War.
Harris endorsed John C. Breckinridge for president in 1860, and warned that the state must consider secession if the "wreckless fanatics of the north" should gain control of the federal government. Following Lincoln's election in November, Harris convened a special session of the legislature on January 7, 1861, which ordered a statewide referendum on whether or not Tennessee should consider secession. Pro-Union newspapers assailed Harris's actions as treasonous. The Huntingdon Carroll Patriot wrote that Harris was more deserving of the gallows than Benedict Arnold. William "Parson" Brownlow, editor of the Knoxville Whig, particularly despised Harris, calling him "Eye Sham" and "King Harris," and slammed his actions as autocratic. When the referendum was held in February, Tennesseans rejected secession by a vote of 68,000 to 59,000.
Following the Battle of Fort Sumter in April 1861, President Lincoln ordered Harris to furnish 50,000 soldiers for the suppression of the rebellion. Reading his response to Lincoln before a raucous crowd in Nashville on April 17, Harris said, "Not a single man will be furnished from Tennessee," and stated he would rather cut off his right arm than sign the order. On April 25, Harris addressed a special session of the state legislature, stating that the Union had been destroyed by the "bloody and tyrannical policies of the Presidential usurper," and called for an end to the state's ties to the United States. Shortly afterward, the legislature authorized Harris to enter into a compact with the new Confederate States of America.
His war-time efforts eventually raised over 100,000 soldiers for the Confederate cause. After the Union Army gained control of Middle and West Tennessee in 1862, Harris spent the remainder of the war on the staffs of various Confederate generals.
The Union Army invaded Tennessee in November 1861, and had gained control of Nashville by February of the following year. Harris and the state legislature moved to Memphis, but after that city fell, Harris joined the staff of General Albert Sidney Johnston. At the Battle of Shiloh on April 6, Harris found Johnston slumping in his saddle and asked if he was wounded, to which Johnston replied "Yes, I fear gravely so." Harris and other staff officers moved the general to a small ravine and attempted to render aid, but Johnston died within a few minutes. Harris and the others secretly moved his body to Shiloh Church so as not to damage the morale of Confederate troops.
Harris spent the remainder of the war as an aide-de-camp on the staffs of various Confederate generals, among them Joseph E. Johnston, Braxton Bragg, John B. Hood, and P.G.T. Beauregard. Andrew Johnson was appointed military governor by President Lincoln in March 1862, though Harris was still recognized as governor by the Confederacy. In 1863, Tennessee's Confederates elected Robert L. Caruthers as a successor to Harris, but Caruthers never took office. Harris was still issuing edicts as governor as late as November 1864.
After the war, the United States Congress passed a joint resolution allowing the governor of Tennessee to offer a reward for the apprehension of Harris because he was “guilty of treason, perjury and theft”. Brownlow, who had become governor, issued a warrant for the arrest of Harris and placed a $5,000 bounty on him. Brownlow taunted Harris in the warrant, stating, "His eyes are deep and penetrating—a perfect index to a heart of a traitor—with the scowl and frown of a demon resting upon his brow. His study of mischief and the practice of crime have brought upon him premature baldness and a gray beard." He further noted that Harris "chews tobacco rapidly and is inordinately fond of liquors."
Harris fled to Mexico, where he and several other ex-Confederates attempted to rally with Emperor Maximilian. After Maximilian's fall in 1867, however, Harris was again forced to flee, this time to England. Later that year, after learning Brownlow would rescind the warrant, Harris returned to Tennessee. Passing through Nashville, he called on Brownlow, who is said to have greeted him with the statement, "While the lamp holds out to burn, the vilest sinner may return." Afterward, he returned to Memphis to practice law.
After returning to Tennessee, Harris became a leader of the state's Bourbon Democrats. During his tenure in the U. S. Senate, he championed states' rights and currency expansion. As the Senate's president pro tempore in the 1890s, Harris led the charge against President Grover Cleveland's attempts to repeal the Sherman Silver Purchase Act.
By 1877, the Tennessee state legislature, which was once again controlled by Democrats, elected Harris to one of the state's U.S. Senate seats.
Harris died in office on July 8, 1897. His funeral was held in the Senate chamber of the United States Capitol and he is interred at Elmwood Cemetery in Memphis, where many prominent West Tennessee political figures are buried.