U.S. Route 425 is a north–south United States highway, first commissioned in 1989. Its route number is a "violation" of the usual AASHTO numbering scheme, as it comes nowhere near its implied "parent", U.S. Route 25.

Another anomaly is US 425's absorption of US 65, forming US 65's southern terminus. The route's northern terminus is in Pine Bluff, Arkansas, at an interchange with Interstate 530/U.S. Route 63/U.S. Route 65/U.S. Route 79/US 65B/AR 190. Until 2005, its southern terminus was in Bastrop, Louisiana, at an intersection with U.S. Route 165. In 2005, it was extended to Natchez, Mississippi, at an intersection with U.S. Route 61.