U.S. 250's northern entrance into West Virginia is via the Military Order of the Purple Heart Bridge from Bridgeport, Ohio onto Wheeling Island. It is briefly co-signed with U.S. Route 40. The route additionally co-signs with Interstate 70 and crosses the Ohio River on the Fort Henry Bridge in Wheeling, West Virginia. U.S. Route 250 then exits I-70 east of the Wheeling Tunnel and joins West Virginia Route 2 one mile (1.6 km) later. In Moundsville, West Virginia, the route leaves WV 2 and departs toward Cameron, Mannington, and Fairmont. It intersects with its parent route, U.S. Route 50, two miles west of Grafton in Pruntytown and continues southward, co-signed with U.S. Route 119 for 12 miles. The route moves through Philippi, and finally through Elkins. U.S. Route 250 intersects with U.S. Route 33 and U.S. Route 219 briefly in Elkins, which is the last major hub before U.S. Route 250 winds its way through the Appalachian Mountains to the Virginia border.