U.S. Route 52 in Virginia runs north–south through the southwestern part of the state along the Interstate 77 corridor.

U.S. 52 enters Virginia from West Virginia, and in Virginia closely follows Interstate 77. It enters southwestern Virginia near Bluefield and passes through Wytheville and Hillsville before leaving the state south of Cana.

The piece of US 52 south of Fort Chiswell was part of the state highway system defined in 1918. It was initially designated State Route 12-Z, at least south of Hillsville, but by 1924 it was State Route 15. In 1926, the U.S. Route 121 designation was applied to the whole length of SR 15, from North Carolina to Fort Chiswell, but it did not turn west on U.S. Route 11 at Fort Chiswell to connect to U.S. Route 21.

An extension of SR 15 from Fort Chiswell north to Max Meadows was added to the state highway system in 1931. In the 1933 renumbering, SR 15 was dropped from the US 121 concurrency, while the short extension to Max Meadows became State Route 121.

US 121 was absorbed by an extension of US 52 by 1935. US 52 was extended through West Virginia and along U.S. Route 21 to Wytheville and U.S. Route 11 to Fort Chiswell, where it replaced US 121 into North Carolina.