US 250 reduces to two lanes and parallels CSX's North Mountain Subdivision on its ascent of Blue Ridge Mountain. Just east of the city limit of Waynesboro, the highway passes under the rail line. Just west of Rockfish Gap, US 250 has a trumpet interchange with I-64, then curves east to the gap itself on the Augusta–Nelson county line. There, the highway has an interchange with the southern end of Skyline Drive, the primary highway through Shenandoah National Park, and the northern terminus of Blue Ridge Parkway. The highway descends the Blue Ridge as Rockfish Gap Turnpike, which runs parallel to I-64 and meets the western terminus of SR 6 (Afton Mountain Road) at Afton before entering Albemarle County. US 250 veers away from I-64, passes under the CSX rail line, and has a junction with the northern end of SR 151 (Critzers Shop Road) at the bottom of the descent. The highway temporarily expands to a four-lane divided highway for its diamond interchange with I-64 at Yancey Mills. In Brownsville, US 250 has an intersection with the western end of SR 240 (Crozet Avenue). The two highways meet again west of Ivy just north of another underpass of the railroad; SR 240 heads west toward Crozet as Three Notch'd Road.