US 250 heads east as a four-lane undivided highway through the southeastern part of Staunton, passing the remains of Western State Hospital and intersecting SR 261 (Statler Boulevard). The highway passes Staunton National Cemetery before expanding to a divided highway, crossing over the North Mountain rail line, and meeting I-81 at a partial cloverleaf interchange just after re-entering Augusta County. US 250 continues as Jefferson Highway, which becomes an undivided highway and passes under the rail line again just before its intersection with SR 285 (Tinkling Spring Road) in Fishersville. The highway becomes Main Street on entering the independent city of Waynesboro. At the west end of the Waynesboro Downtown Historic District, US 250 intersects US 340 (Rosser Avenue); US 340 continues east on Main Street while US 250 turns onto Broad Street, which parallels Main Street one block north and intersects SR 254 (Poplar Avenue). The highway crosses the South River into the Basic City neighborhood of Waynesboro before joining US 340 on Main Street. The two highways pass under Norfolk Southern Railway's Roanoke District and diverge at Delphine Street, where US 340 heads north toward Elkton.