U.S. Route 25E (US 25E) is the eastern branch of US 25 from Newport, Tennessee, where US 25 splits into US 25E and US 25W, to North Corbin, Kentucky, where the two highways rejoin. The highway, however, continues as US 25E for roughly two miles (3.2 km) until it joins Interstate 75 (I-75) in the Laurel County community of North Corbin at exit 29. The highway serves the Appalachia regions of Kentucky's Cumberland Plateau and the Ridge-and-Valley section of East Tennessee, including the urbanized areas of Corbin and Middlesboro in Kentucky and Morristown in Tennessee.

U.S. Route 25 or U.S. Highway 25 (US 25) is a north–south United States Numbered Highway that runs for 750 miles (1,210 km) in the Southern and Midwestern U.S. Its southern terminus is in Brunswick, Georgia, from where it proceeds mostly due north, passing through the cities of Augusta, Georgia; Greenville, South Carolina; and Asheville, North Carolina, before dividing into two branches, known as US 25W and US 25E between Newport, Tennessee, and North Corbin, Kentucky. After passing through Richmond and Lexington, Kentucky, it reaches its northern terminus at Ohio state line in Covington, Kentucky. The route is an important crossing of the Appalachian Mountains, and it is covered by three of the corridors of the Appalachian Development Highway System (ADHS). When the highway was originally established in 1926, the route extended from North Augusta, South Carolina, to Port Huron, Michigan. The southern end was extended to its current terminus in 1936, while the northern end was truncated in 1974.