This protected national wild and scenic river serves as the boundary between Georgia and South Carolina after leaving North Carolina at latitude 35°N. This was set forth in the 1787 Treaty of Beaufort, and interpreted for the Chattooga River in the first Georgia v. South Carolina case before the U.S. Supreme Court in 1922. This came about largely because the Chattooga was not specifically mentioned in the treaty, as it had not yet been surveyed. Had the Chattooga's origin not been at or in North Carolina (which at the time included Tennessee), the far northwestern tip of South Carolina would have extended back to the Mississippi River, north of a due-west line from the river's origin.

The river was used as a setting for the fictional "Cahulawassee River" in the film Deliverance.