From there the route becomes independent and it runs mainly through rural western South Carolina.

Later it crosses a bridge over the Saluda River and is then overlapped with SC 34 until it reaches Newberry.

Barely inside Newberry, the route becomes the terminus of SC 395 and then has a major intersection with US 76.

[8] North of Newberry, it encounters yet another concurrency with US 176, which it follows straight north before curving to the west as it enters Whitmire, where the routes make a sharp turn to the east and encounters the beginning of a long concurrency with SC 72.

This concurrency runs southeast until US 321 branches off to the south at the southern terminus of US 321 Business (US 321 Bus.).

The routes continue to the east along SC 97, running beneath a railroad bridge, and then turning toward the north.

Traversing east of the downtown area, its journey ends at Cherry Road, where US 21 continues north towards Fort Mill, while also connecting with SC 322.

[9][10] The third, and current, SC 121 was established in 1962-1964, which formed a three-state route (continues south as Georgia State Route 121 and Florida State Road 121 to Lebanon Station, Florida).

From North Augusta to Rock Hill, it was placed on concurrencies with various highways throughout the state; with exception around Whitmire, where it replaced part of SC 19.