The highway connects rural areas of Williamsburg County with Greeleyville.

SC 375 begins at an intersection with the southern terminus of SC 377 (Martin Luther King Jr. Avenue) south-southwest of Lane, Williamsburg County, where the roadway continues as Santee Road.

It travels to the northwest and immediately crosses some railroad tracks.

Then, it intersects U.S. Route 52 (US 52; South Williamsburg County Highway).

It then meets its northern terminus, an intersection with US 521 (Society Street).