Upon entering Wythe County, I-81 continues to an interchange with the northern terminus of SR 90 north of the town of Rural Retreat, before reaching a northbound cars-only rest area and passing southeast of the Wythe Raceway. Past the race track, the freeway travels northeast to a northbound exit and southbound entrance with US 11, located west of the town of Wytheville, the county seat of Wythe County. Inside the town limits of Wytheville, I-81 meets an interchange with the northern terminus of US 21 and US 52, where southbound US 52 joins the freeway in a wrong-way concurrency, before it reaches its southern junction with I-77, which heads north from the highway towards Bluefield and Charleston, West Virginia, at a trumpet interchange.