Eastbound US 58 merges onto northbound I-81 to form a concurrency that continues northeast to a directional stack interchange with the northern terminus of I-381, an auxiliary Interstate Highway that serves downtown Bristol to the south.

The freeway heads into a mix of commercial and residential areas where it has interchanges with US 11/US 19 prior to crossing over the Norfolk Southern Railway's Pulaski District, before the route fully enters Washington County.

North of this point are interchanges with US 58 Alternate (US 58 Alt)/SR 75, providing access to the Virginia Creeper Trail and Barter Theatre and with US 11, where eastbound US 58 splits from I-81 continuing east toward the town of Damascus.

[2] At this point, I-77 joins I-81/US 52 in a wrong-way concurrency as the route expands to six lanes and deviates slightly to the southeast of its original heading, before picking up US 11 at another trumpet interchange, a short distance later.

Northbound US 11 joins the extensive wrong-way concurrency as it crosses the Pulaski District line and zigzags away from Wytheville to an interchange with two state frontage roads, SR F042/SR F043.

The median narrows to a Jersey barrier as the freeway comes to an interchange with the southern terminus of SR 121, where southbound US 52 splits from the concurrency to serve the unincorporated town of Fort Chiswell.

Following the northern junction with I-77, the freeway resumes its northeasterly course, regains its median, and reduces back to four lanes as it comes to an interchange with SR 619 north of the hamlet of Graham's Forge.

I-81 again continues by itself, coming to an interchange with SR 660 north of Claytor Lake State Park, before it crosses a bridge dedicated to Trooper Andrew Fox over the New River and leaves Pulaski County.

The freeway continues and meets an interchange with SR 8 that also provides access to the Montgomery Museum of Art & History and the Blue Ridge Parkway, before entering the town limits of Christiansburg.

Shortly afterward, I-81 comes a large cloverleaf interchange for US 11, US 460, and Parkway Drive, where it splits with the outer lanes becoming a collector–distributor road, which US 11/US 460 briefly run along; southbound US 11/westbound US 460 provides to the main campus of Virginia Tech in the nearby town of Blacksburg.

A short distance later, northbound US 11/eastbound US 460 split at another interchange and provide access to the communities of Shawsville and Elliston, while the freeway's collector–distributor carriageways ends and it enters widing alignments that heads toward the valley of the Roanoke River.

Beyond the weigh station, I-81/US 220 crosses the Cloverdale Branch of Norfolk Southern Railway's Roanoke District rail line, prior to reaching an interchange with US 11 and northern terminus of US 220 Alt, which heads south toward the unincorporated city of Cloverdale, also providing access to the city of Lynchburg and the National D-Day Memorial via US 460, where northbound US 220 splits and heads north toward the town of Fincastle, the county seat of Botetourt County, southwest of the town of Troutville.

The freeway continues to interchanges with SR 654 east of unincorporated village of Mint Spring and the southern terminus of SR 262, which also provides access to US 11, before coming a direction stack interchange with the northern junction of I-64, where that eastbound route splits from northbound I-81 and heads toward Richmond, the capital of the commonwealth of Virginia, also providing access to the Blue Ridge Parkway, Skyline Drive, and Shenandoah National Park, as well as the independent cities of Waynesboro and Charlottesville.

Shortly past the split with I-64, I-81 becomes the eastern boundary of the independent city of Staunton, crosses over the Buckingham Branch Railroad's North Mountain Subdivision rail line, and reaches an interchange with US 250 that provides access to the Frontier Culture Museum and the Woodrow Wilson Presidential Library, as well as the campusses of the Virginia School for the Deaf and the Blind and Mary Baldwin University.

[2] The freeway enters Rockingham County, where it crosses the North River and meets SR 257/SR 682 at an interchange, east of the town of Mount Crawford that also provides access to Bridgewater College.

The freeway heads back into rural surroundings, where it meets another interchange with US 11, providing access to the southern terminus of SR 259 serving the towns of Broadway and Timberville, as well as the Endless Caverns site, in the hamlet of Mauzy.

Within the Strasburg area, the freeway interchanges US 48/SR 55, as well as US 11, which provides access to Cedar Creek and Belle Grove National Historical Park, before crossing over CSX Transportation's Shenandoah Subdivision rail line.

[3] On January 8, 2019, Governor Ralph Northam and Republican lawmakers agreed to a plan to add tolls to I-81 in Virginia in order to fund improvements to I-81 and parallel routes that would reduce traffic jams.