U.S. Route 425 (US 425) is a north–south United States highway that travels in the U.S. states of Mississippi, Louisiana, and Arkansas. It was first commissioned in 1989.

U.S. Route 65 is a north–south United States highway in the southern and midwestern United States. The southern terminus of the route is at U.S. Route 425 in Clayton, Louisiana. The northern terminus is at Interstate 35 just south of Interstate 90 in Albert Lea, Minnesota. Parts of its modern route in Iowa and historic route in Minnesota follow the old Jefferson Highway.