Its original commander was John C. Breckinridge, former United States vice president, and Kentucky's former senator, who was enormously popular with Kentuckians.

Units of the Orphan Brigade were involved in many military engagements in the American South during the war, including the Battle of Shiloh.

At the Battle of Stones River, the brigade suffered heavy casualties in an assault on January 2, 1863, including General Hanson.

Breckinridge—who vehemently disputed the order to charge with the army's commander, General Braxton Bragg—rode among the survivors, crying out repeatedly, "My poor Orphans!

The Orphan Brigade lost another commander at the Battle of Chickamauga, when Brigadier General Benjamin H. Helm, Abraham Lincoln's brother-in-law, was mortally wounded on September 20, 1863, and died the following day.