With the approach of the Civil War Breckenridge was a proponent of conciliation and compromise. Finally forced to choose one side or the other, his southern sympathies won out and by the fall of 1861, he left Kentucky and joined the southern cause.

Breckenridge was commissioned a Brigadier General and saw action at Shiloh, Stones River, Chickamauga, and Lookout Mountain. He is best remembered for the Battle of New Market in Virginia. He led Confederate forces, including cadets from Virginia Military Institute and soundly beat back the Union Army of General Franz Sigel, saving the resources of the Shenandoah Valley for vital weeks.

He finally disbanded the Confederate Government on May 4, 1865 and made his escape to Cuba under extremely difficult circumstances. Three years later he returned from exile, to his native Kentucky and resumed his practice of law, as well as becoming active in other enterprises. Breckenridge always spoke out for conciliation and moderation. Robert E. Lee spoke of him as “a lofty, pure, strong man …a great man.”