On the outbreak of the war, Reynolds was commissioned as colonel of the 10th Indiana (militia). He advanced quickly to become a brigadier general. In September he served in command at the Battle of Cheat Mountain, and in the next month at the Battle of Greenbrier River. In recognition, he received a promotion to major general. He was transferred to command a division of the XIV Corps, which he led into Battle at Chickamauga. In October 1863, he became chief of staff of the Army of the Cumberland. In January 1864, he was transferred to command of the New Orleans defenses. He took command of the XIX Corps in the campaign against Mobile. In November 1864, Reynolds was given his last assignment of the war as commander of the Department of Arkansas.