The first segment, traveling north–south, connects the cities of Georgetown and Florence, via the towns of Hemingway, Johnsonville, and Pamplico.

Traveling in a northwesterly direction, along Browns Ferry Road, it merges onto SC 41 in Rhems.

In Florence, SC 51 connects with US 301 (Freedom Boulevard) and US 52 (Irby Street); it then travels west along Second Loop Road to US 76 where it ends.

[2][3][4][5] The York County segment of SC 51 is a short one-mile (1.6 km) road that starts at US 21 near Fort Mill and ends at the North Carolina state line, where it continues on as NC 51 through Pineville.

In the prior year, US 21 was rerouted northwest onto a new freeway route into North Carolina and its old alignment through Pineville was replaced by an extension of NC 51 to the state line.

South Carolina reciprocated with SC 51, keeping the route number consistent across the border.