U.S. Route 52 is a United States highway that runs across the northern, eastern and southeastern regions of the United States. Contrary to most other even-numbered U.S. Highways, US 52 primarily follows a northwest–southeast route, and is signed north–south or east–west depending on the local orientation of the route.

The highway's northwestern terminus is at Portal, North Dakota, on the Canadian border, where it continues as Saskatchewan Highway 39. The southeastern terminus of US 52 is in Charleston, South Carolina, at Number 2 Meeting Street and White Point Gardens along the Charleston Harbor.