On February 20, 1861, S.D. Lee resigned his commission in the U.S. Army to enter Confederate service as a captain. He served as a aide-de-camp to Gen. P.G.T. Beauregard, during which time he carried the demand for the surrender of Fort Sumter. In 1862, he served in the defense of Richmond at the Battle of Seven Pines, and the Seven Days. He served as an artillery commander a the Battle of Second Manassas, and later, at the Battle of Antietam. In November, he was promoted to brigadier general, during which time he participated in the battles of Chickasaw Bayou and Champion Hills. During the siege of Vicksburg, he was captured, but soon after, he was exchanged in August 1863. Upon his return, he received a promotion to major general. The following year, in June 1864, he was promoted to lieutenant general, in charge of the Department of Mississippi and Alabama. In late 1864, he took over command of the Army of Tennessee. He surrendered his army in North Carolina in April 1865.