When the American Civil War began in 1861, Fuller chose to follow his home state and the Union cause. He was ordered to train soldiers in Grafton, Virginia, which is in modern-day Taylor County, West Virginia. He also briefly served on the staff of Brig. Gen. Charles W. Hill. On August 18, Fuller was given command of the 27th Ohio Infantry with the rank of colonel. Fuller and the 27th first served in Missouri under Brig. Gens. John Pope and David Hunter. He and his command then participated in Pope's efforts at New Madrid on March 14, and then the Battle of Island Number Ten from February 28 to April 8, 1862.