U.S. Route 425 (US 425) is a north–south U.S. Highway that traverses the southern United States, spanning the states of Mississippi, Louisiana, and Arkansas. It runs approximately 220 miles from its southern terminus at Natchez, Mississippi, where it intersects with US 61 and US 84, to its northern end near Pine Bluff, Arkansas, at an intersection with US 65. Although not one of the oldest highways in the U.S. system, US 425 has grown in regional importance as a connector through rural communities and agricultural corridors.

The route winds through the heart of the Mississippi Delta and Deltaic Plain, offering access to smaller towns such as Winnsboro and Bastrop in Louisiana and Hamburg and Monticello in Arkansas. The highway often runs concurrent with other routes, such as LA 15 in Louisiana and US 82 near Crossett, Arkansas. While most of the roadway is two-lane, several segments—particularly near urban areas—have been upgraded to four-lane divided highways for improved traffic flow and safety.

US 425 is not a part of the original 1926 U.S. Highway system; it was commissioned later, with significant portions designated in the 1980s and 1990s. Today, it serves as a vital north–south alternative to more heavily trafficked corridors like US 65 and US 61, and it plays an essential role in local economies tied to agriculture, forestry, and manufacturing.