It was successively commanded by Colonels Christopher Mott, Lucius Lamar, Nathaniel Harris, Thomas Hardin, and Richard Phipps.

The regiment was organized by law partners Lucius Q. C. Lamar, a professor at the University of Mississippi, and Christopher Mott, a veteran of the Mexican War.

As part of the Army of Northern Virginia, the 19th Mississippi first fought at the Battle of Williamsburg in May, 1862, where Colonel Mott was killed.

Under General Carnot Posey, the Regiment arrived at Gettysburg to join the second day of the battle, participating in heavy fighting before retreating with the rest of Lee's army to Virginia.

The Regiment held a supporting position at the Battle of Cold Harbor and afterward they were moved to Petersburg, Virginia to join the defensive line there.