It runs for 516.9 miles (831.9 km) from Hardeeville, South Carolina to Lenoir City, Tennessee; with both serving as southern termini.

The route goes through to communities of Winnsboro, Chester, York, and Clover before entering North Carolina at Bowling Green.

Travelers from South Carolina who are going to points west of Charlotte and want to avoid the traffic of I-77 may choose to enter the state on US 321.

The North Carolina Department of Transportation (NCDOT) has a long-term plan to widen the road to six lanes, which is expected to begin after 2020.

[5] North of Lenoir, US 321 is a four-lane divided highway, continuing up the steep escarpment of the Blue Ridge Mountains.

The final portion of the widening project, at the steepest part of the road just south of Blowing Rock, began in 2012 and was completed in 2018.

[7] Some landscaping work remains which will commence in Fall 2018 as its own project, constructed separately for beautification of the route through town.

As it crosses into Tennessee, US 321 enters the Cherokee National Forest, and continues westward through the rugged valley between Pond Mountain on the south and Watauga Lake on the north.

The highway passes numerous campgrounds, boat launches, and other lake-related recreational areas as it winds its way along the shores of the lake.

The Appalachian Trail crosses US 321 at its intersection with Shook Gap Road, just before the highway exits the national forest.

The stretch of US 321 from Newport south to Cosby and southwest through Pittman Center to Gatlinburg parallels the northern boundary of the Great Smoky Mountains National Park and is quite scenic.

In Pigeon Forge, concurrent with US 441/Great Smoky Mountains Parkway, US 321 is a divided, multi-lane traffic-laden thoroughfare where it serves as the city's main route, lined with hotels, outlet malls and amusement facilities.

Veering southwest of Pigeon Forge, the highway takes on a more rural character as it traverses Wears Valley, and narrows down to two lanes until its junction with SR 73 Scenic (the Little River Road) at the Townsend entrance to the park.

US 321 has a wrong-way concurrency with SR 95 from a point several miles south of Lenoir City (near Greenback) to its terminus at I-40.

US 321 is a four-lane semi-divided thoroughfare from I-40 and I-75 to the Great Smoky Mountains National Park, except for the 3-mile (4.8 km) stretch near Walland.

In 1999, the remainder of US 321 was moved onto new freeway bypass west of Newton and Conover; at same time, NC 155 was decommissioned and absorbed into US 321 Business.

[15] In addition to the widening project, there have also been talks of a freeway-to-freeway connection with Interstate 85 in Gastonia that would greatly relieve traffic flowing through the junction[citation needed].

[citation needed] U.S. Route 321 Business (US 321 Bus) was established in June 1999, as a renumbering all of NC 155 and part of mainline US 321 in Catawba County.

Traversing 37.2 miles (59.9 km) through Gaston, Lincoln and Catawba counties, it connects the cities and towns of Dallas, High Shoals, Lincolnton, Maiden, Newton, Conover and Hickory.

In 1957, US 321A was extended south, replacing mainline US 321 through Granite Falls and Hudson, ending at its current southern terminus north of the Catawba River.

U.S. Route 321 Business (US 321 Bus) was established 1960 as an upgrade to secondary roads through downtown Blowing Rock; which were originally part of mainline US 321 until about 1954, when it was moved onto a new bypass east.