During the American Civil War, he served in the Army of the Tennessee under Ulysses S. Grant, who was a student of his at the military academy.

Smith was instrumental in Grant's victory at the Battle of Fort Donelson but died in April 1862 due to infection of a non-combat leg injury and subsequent dysentery.

On August 31, 1861, he was commissioned a brigadier general of volunteers and on September 9, 1861, as colonel of the 3rd Regular U.S. Army Infantry.

[7] He served as a division commander in the Department of the Missouri under newly recommissioned Brigadier General Ulysses S. Grant, who had been one of his pupils decades before at West Point.

However, Halleck soon restored Grant to field command (intervention by 16th President Abraham Lincoln may have been a factor).

[14] The untimely death of Gen. Smith forced Grant to partner with General William Tecumseh Sherman, and build a partnership with him that would eventually win the war.

The first Fort C. F. Smith was built in 1863 as part of the perimeter defenses of Washington, D.C. during the American Civil War.

[17] The third Fort C. F. Smith was built in 1866 at the Bighorn River crossing of the Bozeman Trail in the southern edge of the Montana Territory from 1864 to 1889.