Routing Following the spine of the Appalachian Mountains, Interstate 81 provides a major trucking corridor and link from the Southeastern States and Tennessee Valley northward to the Northeastern Megalopolis. Interstate 81 does not enter major metropolitan areas; it instead serves an array of small to mid-size cities.

The route commences from a rural directional T interchange near Dandridge, Tennessee to run northeast across agricultural areas and forest land along the west side of the Appalachian Mountains to the Tri-Cities region. A spur route, I-181, once connected I-81 with Kingsport and Johnson City. It was renumbered in 2003 as a northern extension of Interstate 26 from Asheville, North Carolina. Crossing into Virginia by the two-state city of Bristol, Interstate 81 combines with U.S. 58 through to Abingdon. A short spur, I-381, links I-81 with the Bristol city center as the freeway bypasses the community to the north.

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Further east, Interstate 81 combines with Interstate 77 along a 'wrong-way' overlap, where I-77 south combines with I-81 north and vice versa due to their east-west orientation between Wytheville and Fort Chiswell. I-77 leads north to Charleston, West Virginia and south to Charlotte, adding truck traffic from the Carolinas to Interstate 81 as it progresses northeast to Christiansburg, Roanoke and Lexington. I-581 represents the second urban spur for Interstate 81, as it combines with U.S. 220 south through Roanoke while the parent freeway stays north by Salem.

Interstate 64 combines with I-81 from Lexington northeast to Staunton as part of its east-west route between Beckley, West Virginia and Roanoke, Virginia. Additional truck traffic funnels onto I-81 south from central Virginia via I-64. Shabloni genealogicheskogo dereva dlya shkoljnika. Northward from their overlap, I-81 continues to Harrisonburg, Strasburg and the west end of I-66, and Winchester to exit the state through the Eastern Panhandle West Virginia. The short stretch through the Mountaineer State takes I-81 through the urban area of Martinsburg. The section concludes at the Potomac River and Williamsport, Maryland. The freeway stays urban along the west side of Hagerstown between the crossroads with I-70 and Hagerstown Regional Airport (HGR).

Truck traffic remains heavy as the route enters the Keystone State nearby. Angling northeast, Interstate 81 and its companion U.S. 11 pass through Chambersburg and Carlisle en route to the Harrisburg area. 11 provides the connection to Interstate 76 (Pennsylvania Turnpike) in lieu of direct access as I-81 turns more easterly toward the capital city. 11 meanwhile turns north along the Susquehanna River, leaving the freeway to follow U.S. 22 through to Interstate 78 and an independent route northeast to Hazelton and Wilkes-Barre.

11 rejoins the I-81 corridor at Wilkes-Barre, following surface routes northeast to Scranton while I-81 hugs the east side of the urban area through to Interstates 84 & 380 and the U.S. 6 freeway spur to Carbondale. West from there, I-81 passes between urban Scranton and Dickson City to briefly combine with U.S. 11 through to the north end of Interstate 476 (Pennsylvania Turnpike - Northeast Extension). The remainder of Interstate 81 generally travels north-south along side U.S. 11 between Scranton and the Thousand Islands Bridge into Canada. An urban stretch takes I-81 through the city of Binghamton, where New York 17 / Interstate 86 overlap through to the, a long term rebuild of I-81 & 86 between NY 7 and their split over the west banks of the Chenango River.

I-86 follows the Southern Tier of New York west to Elmira and Corning while I-81 joins Binghamton with Cortland and Syracuse. Through Syracuse, Interstate 81 passes through the city center while Interstate 481 provides a suburban bypass to the east. A is the replacement of the aging viaduct around Downtown or the relocation of I-81 onto I-481 and subsequent conversion of the through route into a combination of urban boulevard and freeway spur. Beyond the city, I-81 travels a mostly rural course east of Lake Ontario to Watertown and the bridge system spanning the St. Lawrence Seaway to the Ontario 401 freeway.

Parallel U.S. 11 parallels freeways for the majority of route from New Orleans north to Watertown, New York. I-81 runs along the US highway from east of Bristol, Virginia through to Upstate New York, with the exception of between Harrisburg and Wilkes-Barre, Pennsylvania. Through Tennessee, U.S. 11 partitions into the branches of 11E and 11W, along the Interstate 81 corridor between Knoxville and Bristol. 22 also parallels the freeway from Harrisburg northeast to I-78 near Jonestown, Pennsylvania. Interstate 81 through Syracuse Constructed in the 1950s and 60s, the 1.4 mile long elevated viaduct of Interstate 81 through Syracuse is deteriorating and in need of replacement.