Born Edmund Kirby Smith, he later signed his name E. Kirby Smith; the hyphenated form of the name was adopted by his family after his death. Graduated from the U.S. Military Academy, West Point, N.Y., in 1845, Kirby-Smith fought in the Mexican War (1846–48) and in Indian warfare on the frontier before he reached the rank of major in 1860. When Florida seceded from the Union (January 1861), he entered the Confederate Army and was made a brigadier general in June. Commanding a brigade at the First Battle of Bull Run (First Manassas; July 1861), he was seriously wounded. In 1862 he led the advance in the Kentucky campaign, defeated the Union forces at Richmond, Ky., and fought at Perryville, Ky., and Stones River (Murfreesboro) in Tennessee. He was promoted to lieutenant general in October and the following February was given command of the Trans-Mississippi Department.

Cut off from the East by the fall of Vicksburg (July 1863), Kirby-Smith exercised both civil and military powers and made his section self-supporting. In April 1864 he met and defeated the Federal Red River expedition. On June 2, 1865, he formally surrendered the last armed Confederate force at Galveston, Texas.

After the war Kirby-Smith headed a military academy until 1870, when he became president of the University of Nashville. He resigned in 1875 to teach mathematics at the University of the South.