After passing Mount Pleasant in eastern Cabarrus County, the road becomes a designated North Carolina Scenic Byway.

The route passes close to Pfeiffer University in Stanly County before crossing the Yadkin River near the Tuckertown Reservoir.

After crossing the river, the road skirts the northern foothills of the ancient Uwharrie Mountains and then drops down into the Asheboro area.

In Ramseur, the two routes split; NC 49 goes north through the towns of Liberty and Alamance and into Burlington, where it meets I-40/I-85.

After passing through Roxboro and a short interval of concurrency with US 158 and US 501, NC 49 continues on toward the Virginia state line.

Established in late 1934 as a renumbering of NC 15, it traversed from Lake Wylie to Morehead and Tryon Street, in Charlotte, where it connected with US 21/US 29/US 74/NC 27.

In 1949, NC 49 was rerouted in Roxboro from Main Street onto newly constructed Madison Boulevard.

From Concord, it went north through Kannapolis and Landis before ending in Salisbury at Main and Innes Street, connecting with NC 10/NC 80.

A spur route of NC 49, it went south near the Tuckertown Reservoir to New London, connecting with US 52/NC 740 on Gold Street.