On November 4, 1775, the regiment was adopted by the Continental Army, and on February 27, 1776, it was assigned to the Southern Department.

It was the main unit involved in the successful defense of Fort Moultrie at the Battle of Sullivan's Island, which prevented Charleston from being attacked by British forces for the next several years.

When the flag designed by the fort's commander, Colonel William Moultrie, was shot down, one of the regiment, William Jasper, grabbed it and held it aloft, rallying the troops until a stand could be provided.

This battle was vital to the entire war, and became symbolic of liberty in South Carolina.

The regiment was captured by the British Army at Charleston on May 12, 1780, together with the rest of the Southern Department.