The highway, signed as north–south, travels in a northwest–southeast direction connecting the cities of Rock Hill, York and Blacksburg.

Going northwesterly nearly its entire route, it crosses the Catawba River entering York County.

In Lesslie, it joins U.S. Route 21 (US 21), crossing over Interstate 77 (I-77) before splitting in Rock Hill.

Continuing on its northwesterly direction, it reaches its final destination of Blacksburg, where it connects with US 29 before ending at I-85 (exit 102) and SC 198.

In 1939, SC 5 reached its longest length with its last extension south along US 21 through Columbia.

Around 2006–2009, SC 5 rerouted to its current northern terminus with I-85/SC 198 in Blacksburg; its old alignment was downgraded to secondary roads.

In 2013, mainline SC 5 was rerouted from downtown Rock Hill and onto the truck route, thus eliminating it.

The highway begins on SC 5 just 1.5 miles (2.4 km) away northwest from downtown York.