In January 1862, the regiment relocated to Camp Dennison for drill instruction. In March, the regiment was assigned to guard Confederate prisoners at Camp Chase. During the Civil War, the regiment shifted command several times, eventually engaging in conflict with General Robert E. Lee and his Confederate forces at the Battle of Gettysburg in July 1863. Following Lee's surrender to General Ulysses S. Grant at Appomattox Courthouse, the regiment escorted Grant from Appomattox to Burkesville Station. In August 1865, the 6th Ohio was mustered out of service in Cleveland. In total, casualties for the 6th Ohio reached 238.