In the months leading up to the American Civil War, Isham Harris, the first West Tennessean elected to the governor's office, championed secession.

When Nashville fell to Union forces, in February of 1862, Harris moved the state government to Memphis. When Memphis fell, Harris again fled, but continued to function as though he assumed himself to be governor as late as November of 1864. Faced with the collapse of the Confederacy in 1865, Harris fled to Mexico where he joined other Confederate expatriates in support of the recently installed Emperor Maximilian Hapsburg. A younger brother to Franz Joseph Hapsburg, Emperor of Austria. Maximilian had invited them.

In flagrant disregard of the longstanding Monroe Doctrine, the French had taken advantage of America's preoccupation with its own Civil War and installed Maximilian as emperor on June 10, 1864.

With Mexico swept by unrest following the withdrawal of French troops, Harris fled once more, this time to England, but returned to the United States in 1867 following a presidential pardon from Andrew Johnson. In Nashville, legendary newspaperman William G. Brownlow, who had fueled the East Tennessee rebellion against the Confederacy, greeted Harris with a line from the old hymn Life is the Time to Serve the Lord by Isaac Watts: "While the lamp holds out to burn, the vilest sinner may return”.

With former Confederates firmly in control of state government, following reconstruction, Tennessee sent Isham Harris to the U.S. Senate in 1877. Harris died, while in office, at Washington D.C., on July 8, 1897, and was buried at Elmwood Cemetery in Memphis.