South Carolina Highway 49 is a primary state highway in the U.S. state of South Carolina. It traverses north–south from Watts Mill to the North Carolina state line, in Lake Wylie.

SC 49 is part of a three-state highway 49, that totals 325 miles (523 km), from Watts Mill, South Carolina to Crewe, Virginia.

Established in 1937 as a renumbering of SC 163; it ran from U.S. Route 321, in York, to the North Carolina state line, in Lake Wylie. In 1956, SC 49 was extended southwest to its current southern terminus at US 221, in Watts Mill; replacing SC 91 from York to Monarch, SC 92 from Monarch to Cross Anchor, and SC 30 from Cross Anchor to Watts Mill.

In 1960 or 1961, SC 49 was rerouted from Lockhart to Mount Tabor. At an unknown date, SC 49 was rerouted north around downtown Union.

One previous SC 49 existed from around 1927-1935, from Myrtle Beach to the North Carolina state line in Little River. In 1932, most of SC 49 north of Myrtle Beach was replaced by US 117; by 1935, the rest of SC 49 (and US 117) was replaced by US 17.