The Cullasaja River is a short river located entirely in Macon County, North Carolina. It is a tributary of the Little Tennessee River (and in turn the Tennessee River and Mississippi River), into which it flows near the county seat of Franklin. It originates to the southeast, near Highlands, the county's only other town. It flows from manmade Lake Sequoyah, which is fed by Mirror Lake and other creeks and streams originating on the western side of the Eastern Continental Divide, which runs through the ease side of town.

A two-lane highway, which is the combined route of U.S. 64 and N.C. 28, runs through the Cullasaja Gorge, which is mostly protected as part of the Nantahala National Forest. The U.S. Forest Service has designated this to be a National Scenic Byway because of the river, and its numerous waterfalls, including:

The road is known as Franklin Road near Highlands, and Highlands Road near Franklin. Three townships are located in the valley below the gorge: Cullasaja, Gneiss, and Sugar Fork. The Cullasaja's largest tributary is most likely Buck Creek. The most well-known is Peek's Creek, where a catastrophic flood and mudslide occurred in September 2004.