The 15th South Carolina's initial trial-by-fire occurred on Hilton Head Island during the Battle of Port Royal Sound on November 7, 1861.

Following the Regiment's service on the coast of South Carolina, the unit was transferred to Robert E. Lee’s Army of Northern Virginia (ANV) in July 1862.

As part of Lee's Army, the 15th SC served in James Longstreet's corps in all of the ANV battles from Second Manassas onward, including Sharpsburg and South Mountain.

In April 1864, the 15th SC and the rest of Kershaw's brigade returned to Lee's Army of Northern Virginia command and fought in the battles of the Wilderness, Spotsylvania, North Anna, Cold Harbour and the siege of Petersburg.

In August 1864, Lee ordered Kershaw's brigade to the Shenandoah Valley where the men fought in the battles at Charlestown, Strasburg's Hupp's Hill and Cedar Creek.