SR 49 joins US 58, a four-lane divided highway, in a concurrency to just west of Clarksville. SR 49 heads northeast along Virginia Avenue, which also carried US 58 prior to the completion of US 58's Clarksville bypass. Virginia Avenue is a four-lane divided highway from US 58 into the town of Clarksville until just after it passes under the Virginia Southern Railroad, where the highway reduces to two lanes and intersects US 15 (College Avenue). SR 49 and US 15 continue east concurrent into downtown Clarksville, where the highway passes through the Clarksville Historic District. After passing through the downtown area, SR 49 and US 15 leave the town of Clarksville by crossing the John H. Kerr Reservoir, an impoundment of the Roanoke River that is also known as Buggs Island Lake, on the Phillip Saint Julian Wilson Bridge and a causeway. The bridge, which contains lights underneath used for nighttime fishing, includes a brief passage through Halifax County due to the thalwegs of the Roanoke and Dan Rivers, which were used to set the county boundaries, converging just south of Clarksville. At the east end of the causeway, access to US 58 is provided at a four-way intersection. Ramps to US 58 west and US 58 east form the southern and eastern legs of the intersection, which mainline US 58 avoids via a pair of flyover ramps just east of its bridge over the reservoir. SR 49 and US 15 turn north, cross over the Virginia Southern rail line, and parallel the eastern shore of the lake until the two highways split at the hamlet of Dortch Store.