The regiment was formed in March 1862, and initially assigned to defensive duty in South Carolina.

It was engaged at the Battle of Secessionville near Charleston before being sent northward for duty in Virginia.

After the Battle of Antietam in September, Robert E. Lee decided to reorganize his army for more efficiency, and the 51st Regiment was permanently assigned to Paul Jones Semmes's brigade.

The subsequent brigade commanders were Goode Bryan and James P. Simms.

The regiment was a part of the Army of Northern Virginia from July 1862 until its surrender at Appomattox Court House, except during James Longstreet's 1863 independent expedition to Georgia and East Tennessee.