The highway connects rural areas of McCormick County with Greenville, via Calhoun Falls, Iva, Homeland Park, and Anderson.

This intersection is within Sumter National Forest and just north of SC 28's crossing of Long Cane Creek.

It then curves to the southwest, passes just to the west of the John de la Howe School, and crosses the Little River.

Just before Turman road, it leaves the national forest proper and begins traveling along the western edge of it.

There, it crosses over Bell Creek and then intersects SC 823, which is east of Mount Carmel Cemetery.

It passes Calhoun Falls Charter School and Edgewood Park.

Upon leaving town, it passes Calhoun Falls State Park and then Salem Cemetery and curves to the north-northwest.

Then, SC 81 enters Lowndesville, where it curves to a northwesterly routing east of Providence Cemetery.

The highway begins curving to the north-northeast and passes Crescent High School.

The highway curves again to the north-northeast and passes Homeland Park Elementary School.

SC 81 heads in a fairly northerly direction and passes Orr Mill Park just before entering Anderson.

The five-highway concurrency intersects the eastern terminus of SC 24 (Whitner Street).

and SC 81 pass AnMed Health Medical Center and then split at a point west of Anderson University.

When, it crosses over the Saluda River, not only does it leave Powdersville, it enters Greenville County.

It passes Carolina High School and Academy just before it intersects US 25 (White Horse Road).