From 1856 to 1860, Wise served as the governor of Virginia. In June 1861, he volunteered and was appointed brigadier general. He served in the campaign in western Virginia, and subsequently, his command was moved to North Carolina. He served in the defense of Charleston, South Carolina, before heading south to Florida. In May 1864, he came north to serve in the defense of Richmond. He served at the battle of Drewry's Bluff, and later, at the Battle of Saylor's Creek as a division commander. He served until the surrender two days later.