U.S. Route 58 is an east–west U.S. Highway that runs for 508 miles (818 km) from U.S. Route 25E just northwest of Harrogate, Tennessee, to U.S. Route 60 in Virginia Beach, Virginia. Until 1996, when the Cumberland Gap Tunnel opened, US 58 ran only inside the commonwealth of Virginia. It was then extended southwest along a short piece of former US 25E, which no longer enters Virginia, to end at the new alignment in Tennessee. For most of its alignment, it closely parallels Virginia's southern border with North Carolina.
U.S. Route 11E (US 11E) is a divided highway of US 11 in the U.S. states of Tennessee and Virginia. The United States Numbered Highway, which is complemented by US 11W to the north and west, runs 120.94 miles (194.63 km) from US 11, US 11W, and US 70 in Knoxville, Tennessee, north and east to US 11, US 11W, US 19, and US 421 in Bristol, Virginia. US 11E connects Knoxville and the twin cities of Bristol, Virginia, and Bristol, Tennessee, with the East Tennessee communities of Morristown, Greeneville, and Johnson City. The U.S. Highway runs concurrently with US 70 and US 25W east of Knoxville, US 321 from Greeneville and Johnson City, and both US 19W and US 19 between Johnson City and Bristol. US 11E also has an unsigned concurrency with State Route 34 (SR 34) for almost all of its course in Tennessee.
U.S. Route 25E (US 25E) is the eastern branch of US 25 from Newport, Tennessee, where US 25 splits into US 25E and US 25W, to North Corbin, Kentucky, where the two highways rejoin. The highway, however, continues as US 25E for roughly two miles (3.2 km) until it joins Interstate 75 (I-75) in the Laurel County community of North Corbin at exit 29. The highway serves the Appalachia regions of Kentucky's Cumberland Plateau and the Ridge-and-Valley section of East Tennessee, including the urbanized areas of Corbin and Middlesboro in Kentucky and Morristown in Tennessee.
Interstate 81 (I-81) is part of the Interstate Highway System that runs 855.02 miles (1,376.02 km) northward from Dandridge, Tennessee, to the Thousand Islands Bridge at the Canadian border near Fishers Landing, New York. In Tennessee, I-81 serves the northeastern part of the state, running 75.66 miles (121.76 km) from its southern terminus with I-40 in Dandridge to the Virginia state line in Bristol. The route serves the Tri-Cities region of the state and the eastern parts of the Knoxville metropolitan area, terminating about 35 miles (56 km) east of Knoxville. I-81 bypasses most cities that it serves, instead providing access via interchanges with state and federal routes. It remains in the Ridge-and-Valley topographic region of the Appalachian Mountains for its entire length in Tennessee, and runs in a northeast to southwest direction.
State Route 66 is a state-maintained highway in eastern Tennessee, including a six-lane divided highway known as Winfield Dunn Parkway in Sevier County, a four-lane expressway in Hamblen and Jefferson counties and a two-lane rural collector through mountainous terrain continuing to the northeast terminus in Hancock County.
U.S. Route 27 in Tennessee runs from the Georgia state line in Chattanooga to the Kentucky state line in Isham. It forms the informal border between the Eastern and Central Time Zones of the state. However, it stays in the Eastern Time Zone.
In Tennessee, U.S. Route 412 stretches for 181.93 miles (292.79 km) through the farmland of West Tennessee and the hills of Middle Tennessee, starting at the Missouri state line near Dyersburg and running to an interchange between I-65 and SR 99 in Columbia.
State Route 70 is a state-maintained highway in East Tennessee, beginning at the border with North Carolina in the midst of the Cherokee National Forest and the Great Smoky Mountains and ending at the Virginia border in the extremely rural and mountainous terrain of Hancock County.
State Route 107 is a 78.77-mile (126.77 km) state highway in eastern Tennessee, United States. It begins at an intersection with Round Mountain Road south of Del Rio and ends at the North Carolina state line east of Unicoi, where it becomes NC 226.
U.S. Route 127 in Tennessee is a 129.5-mile-long (208.4 km) United States Numbered Highway from Chattanooga to the Kentucky state line at Static. The highways connects through Dunlap, Pikeville, Crossville, and Jamestown. Throughout its length, US 127 straddles the line between East Tennessee and Middle Tennessee.
State Route 186 is a state highway in the U.S. state of Tennessee. It runs from Trenton southward to Jackson, passing through the towns of Gibson and Three Way along the way. The southern portion serves as a western bypass for the city of Jackson, which is signed as U.S. Route 45 Bypass.
State Route 32 is a state highway in East Tennessee. For most of its route, it is an unsigned companion route concurrent with U.S. Route 25E. The highway stretches 89 miles from the North Carolina state line to the Tennessee-Kentucky state line near the town of Cumberland Gap.
State Route 126 is a 24.6-mile-long (39.6 km) state highway that travels through Sullivan County in East Tennessee. It connects Kingsport and Bristol.
State Route 113 is a north–south state highway in East Tennessee.
State Route 340 is a state highway in the eastern portion of the U.S. state of Tennessee. It travels south-to-north through portions of Cocke, Greene and Hamblen counties.
State Route 343 is a state highway in Morristown, Hamblen County in the U.S. state of Tennessee. It serves as connector from US 25E into downtown Morristown.
State Route 474 was a 1.4-mile-long (2.3 km) five-lane state highway in Hamblen County in the eastern portion of the U.S. state of Tennessee. It served as a connector route from SR 160 to US 11E/SR 34. It was decommissioned and designated as part of SR 66 following an extension project by TDOT in November 2020.
U.S. Route 231 in Tennessee runs north–south for 121.15 miles (194.97 km), entirely in Middle Tennessee, that starts south of Fayetteville at the Alabama state line, and ends north of Westmoreland at the Kentucky state line. For the majority of its length, between the Alabama state line and Trousdale County, it is concurrent with unsigned State Route 10.
State Route 222 is a 12.9 miles (20.8 km) long north-south state highway in southern West Tennessee. It connects the towns of Somerville and Stanton with Interstate 40.
The East Tennessee Crossing Byway is a 83-mile (134 km) National Scenic Byway in the U.S. state of Tennessee. Established in 2009, it is one of the newest byways in the National Scenic Byway system. The scenic byway traverses mostly along an unsigned concurrency of U.S. Route 25E/State Route 32 (US 25E/SR 32) in East Tennessee.
US 11E in Morristown 
US 321 near Newport 
