U.S. Route 49 is a north–south United States highway. The highway's northern terminus is in Piggott, Arkansas, at an intersection with US Route 62/Highway 1/Highway 139 (US 62/AR 1/AR 139). Its southern terminus is in Gulfport, Mississippi, at an intersection with U.S. Route 90. US 49 is approximately 516 miles (830 km) in length.

It was at the junction of US 49 and U.S. Route 61 that blues singer Robert Johnson is said to have sold his soul to the Devil. The highway is also the subject of songs by Big Joe Williams and Howlin' Wolf.