Mustered-in December 14, 1861, and ordered immediately to the Army of the Cumberland, where it was assigned to General O. M. Mitchel's Division. In the summer of 1862, Mitchel's troops marched through Kentucky and Tennessee to Huntsville, Ala.; thence, with Buell's Army, on the campaign incidental to the pursuit of Bragg, marching north, across Tennessee and Kentucky, to Louisville; and thence to Perryville, Ky., where the battle of Chaplin Hills was fought. The regiment was then in Lytle's Brigade, Rousseau's Division, McCook's Corps, and sustained a fearful loss in that battle, its casualties amounting to 66 killed, and 130 wounded; no missing. The three field-officers, Colonel Pope, Lieutenant-Colonel George P. Jouett, and Major William P. Campbell, were killed in this battle; two of the line-officers also lost their lives there. The Fifteenth carried itself through this bloody action with a cool gallantry and steadiness of movement which elicited strong words of praise in the official reports of that action.

At Stone's River, the regiment lost 10 killed, 32 wounded, and 18 missing; Forman, the "Brave Boy Colonel," being among the killed. At Chickamauga, then in Beatty's (1st) Brigade, Negley's (2d) Division, Fourteenth Corps, the regiment lost 5 killed, 42 wounded, and 15 missing. In October, 1863, it was placed in Carlin's (1st) Brigade, Palmer's (1st) Division, Fourteenth Corps, in which command it fought at Missionary Ridge. During the Atlanta campaign, this division was known as Johnson's Division. After the fall of Atlanta, the regiment was assigned to garrison duty. Mustered out January 14, 1865.