In Tennessee, U.S. Route 64 (US 64) stretches from the Mississippi River at the Arkansas state line in Memphis to the North Carolina state line near Ducktown. US 64 is the major east-west transportation corridor across the southern part of Tennessee, entering the state in Memphis, the second largest city in Tennessee, and passing through the fourth-largest city of Chattanooga in the east. The highway also serves several smaller towns in between. US 64 passes through the state's three Grand Divisions. Most of US 64 in Tennessee has been expanded to four lanes, and is part of the National Highway System. West of Chattanooga, US 64 crosses the Cumberland Plateau concurrent with I-24 on a section of highway known as Monteagle Mountain. This section features steep grades, and is considered one of the most dangerous stretches of the Interstate Highway System. The eastern section between Cleveland and the North Carolina state line is part of Corridor K of the Appalachian Development Highway System. In East Tennessee, US 64 also features multiple scenic routes, including the Tennessee River Gorge along the Tennessee River through the Cumberland Plateau and the Ocoee Scenic Byway, a National Forest Scenic Byway along the Ocoee River through the Blue Ridge Mountains.

US 64 evolved from a series of Native American trails that were later used by European American settlers. Another predecessor was the Old Copper Road, constructed in the eastern part of the state between 1851 and 1853 to transport mined copper from the Copper Basin region. US 64 was established in Tennessee with the United States Numbered Highway System in 1926, and quickly became a major transportation corridor. Parts of the Old Copper Road section were improved with funding from the Appalachian Regional Development Act of 1965. This legislation also proposed expanding the section through the Blue Ridge Mountains to a four-lane highway, but this has faced extensive opposition related to cost and environmental concerns. In the later part of the 20th century, the state conducted studies that showed the need for a modern transportation corridor across the southern rural counties in Tennessee. Planning began in 1980, and in 1986, initial funds were allocated to begin widening the section between Memphis and I-24 west of Chattanooga to a four-lane highway as part of a major road funding effort by the Tennessee General Assembly. The project was completed in 2017 at a cost of approximately $1.26 billion. Other major projects include safety improvements in the mountainous stretches and initiatives to relieve congestion in urban areas.

Route description Memphis and Shelby County

US 64 enters Tennessee on the Memphis & Arkansas Bridge in Memphis. The route shares the bridge with Interstate 55 (I-55) and US 61, US 70, US 78, and US 79. Immediately east of the bridge, the routes split off onto Crump Boulevard, a four-lane surface street with a center turn lane. A few blocks later, the highway turns north onto B. B. King Boulevard, where US 61 splits off to the south as Third Street, and US 78 continues to the east. The road briefly shrinks to two lanes under a railroad underpass, before entering downtown and splitting into a one-way pair of three-lane streets. US 64/70/79 then turn east onto Union Avenue and have an interchange with US 51 (Danny Thomas Boulevard) a short distance beyond, beginning a concurrency with this road. A short distance beyond this is an interchange with I-240. Passing through a commercial area, US 51 splits off to the south as Bellevue Boulevard, and the road expands to a six-lane surface boulevard a few blocks beyond this. After a short distance, the US routes turn north onto North Parkway, part of the Memphis Parkway System, at an interchange with this road.

Continuing north as a four lane divided highway, the highways meet the western terminus of US 72 (Poplar Avenue) a short distance beyond. The road then passes along the eastern boundary of Overton Park, and intersects the western terminus of Sam Cooper Boulevard, before turning east onto Summer Avenue, a four-lane boulevard with a center turn lane. Passing through a predominately residential area lined with commercial establishments, the road expands to six lanes after several blocks, before reaching a partial interchange with I-40 and reducing two four lanes. Here only the westbound lanes of I-40 connect to US 64/70/79, and the eastbound access is via White Station Road. The highway then turns northeast and crosses the Wolf River. The highway passes through suburban neighborhoods of eastern Shelby County on the edge of Bartlett. A few miles later, US 64 turns east at an intersection with SR 15 (Stage Road), beginning an unsigned concurrency with this road. Here, US 70/79 continue to the northeast, and US 64 proceeds east as a six-lane highway. Passing along the edge of Germantown, US 64 intersects SR 177 (Germantown Parkway), a major north-south thoroughfare, before reaching an interchange with I-40 once again. Continuing through additional neighborhoods, the highway reduces back to four lanes a short distance later, before entering a less developed area. Several miles later is an interchange with I-269, a partial outer beltway around Memphis, and US 64 enters Fayette County immediately beyond.

Southwest Tennessee and Gulf Coastal Plain Upon entering Fayette County, US 64 becomes a divided four-lane highway, with the center turn lane ending. US 64 then passes through Hickory Withe and has a junction with SR 196. They then enter Oakland and have an intersection with SR 194, before continuing east. They continue through rural farmland, passing by Glengary Lake. US 64 then enter Somerville and have an intersection with SR 76 in downtown. They then pass through Laconia, where they cross over the Loosahatchie River, before crossing into Hardeman County.

They then enter Whiteville, where US 64 Business (US 64 Bus) begins and goes east through downtown while US 64 follows a new bypass to the south. It also junctions with SR 179. The highway then meets up with the other end of US 64 Bus and goes east to have an intersection with SR 100, before US 64 leaves Whitville and continues southeast. It then enters Bolivar and becomes concurrent with SR 18. The highways then enter downtown and have a junction with SR 125, with SR 18 splitting off and going north along that highway. US 64 then leaves Bolivar and continues east. The higheay goes through some wooded areas, where it crosses the Hatchie River, and passes through Hornsby before crossing into McNairy County.

They then intersect SR 225 before going through some rural wooded areas and then entering Selmer, at an interchange with US 45/SR 5, which US 64 follows as a new bypass to the south while SR 15 goes through downtown, signed as US 64 Bus. SR 15 then goes east through downtown and comes to another junction with US 45/US 64/SR 5, with the road continuing east as US 45/SR 5 and SR 15 joins US 64 again, and they go northeast. US 64/SR 15 then intersect and have a short concurrency with SR 224 just north of Stantonville before entering Adamsville. In Adamsville, they have an intersection with SR 22 and SR 117 in the center of town, with SR 22 joining the concurrency. US 64/SR 15/SR 22 then leave Adamsville and cross into Hardin County. They then enter Crump and have an intersection and become concurrent with SR 69. A short distance later, SR 22 branches off and turns south. They then run along the banks of the Tennessee River before crossing it and entering Savannah.

Southern Middle Tennessee and Highland Rim Upon crossing the river, US 64 immediately enters downtown Savannah and passes by the Tennessee River Museum, becoming concurrent with SR 128 before coming to an intersection with SR 203, where SR 69 turns south, SR 203 goes east, and US 64/SR 15/SR 128 go northeast to leave Savannah. They then intersect SR 226 before north of Olivet before SR 128 splits off and goes north. US 64/SR 15 then go through some mountains and pass through Olivehill before crossing into Wayne County.

They enter Clifton Junction where they intersect US 641/SR 114. US 64/SR 15 then go through a narrow valley before entering Waynesboro, bypassing the city to the west and north. It then has an interchange with SR 13 and crosses over the Green River before going east to intersect with SR 99. US 64/SR 15 then leave Waynesboro and continue east through mountainous terrain. They then enter some farmland and have an interchange with the Natchez Trace Parkway just before crossing into Lawrence County.

They then intersect with SR 240 in Deerfield and then SR 241 just a little further to the east. They then enter Lawrenceburg. Just west of downtown, US 64 Bus begins and goes east into downtown, while US 64/SR 15 follow a new bypass to the south. They then have an interchange with SR 242 and cross over Shoal Creek, just south of New Shoal Creek Dam, shortly thereafter. They then have an interchange with US 43/SR 6 before passing through largely rural areas. They then come back around to meet the other end of US 64 Bus before leaving Lawrenceburg and continuing east through more mountains. US 64/SR 15 then cross into Giles County.

It then passes through Bodenham before intersecting and becoming concurrent with SR 166 and entering Pulaski. US 64 then bypasses the city to the south with SR 15/SR 166 going into downtown. SR 166 splits and turns south at an intersection with SR 11, with SR 11 becoming concurrent with SR 15. They then come to an intersection with US 31/SR 7, where SR 11 splits off and goes north along that highway. SR 15 then goes east back to US 64, where they continue east together. They go through some more mountains before coming to an interchange with I-65 (Exit 14) in Frankewing. US 64/SR 15 then cross into Lincoln County.

They then pass through Boonshill and intersect with SR 244. They then intersect with SR 273 before entering Fayetteville and coming to an intersection with US 64 Bypass (US 64 Byp), a new southern bypass of the city. US 64/SR 15 then go through downtown to intersect SR 50/US 431 and become concurrent with SR 50. They then come to another intersection with US 64 Byp, which at this point is also concurrent with US 231/SR 10. SR 50 then splits off and goes north at another intersection before US 64/SR 15 go east and leave Fayetteville. They continue east through farmland and mountains to cross the Elk River before passing through Kelso. They then pass just north of Flintville and junction with SR 275. They then intersect and have a short concurrency with SR 121 before entering Franklin County.

US 64/SR 15 then enter Huntland, where they have a junction with SR 122 and SR 97. They then pass through Belvidere before entering Winchester and having an interchange with SR 16, which provides access to downtown as US 64/SR 433 bypass it to the southeast, and SR 15 splits from US 64 again to follow SR 16. US 64 continues on its bypass around Winchester, and then bypasses Decherd, where it has an interchange with a connector road to the Nissan power train plant. The highway continues through farmland for several miles, before reaching an interchange with I-24 in Pelham and begins a concurrency with that route. Here, the highway continues past this interchange as SR 50.

Monteagle Mountain and Tennessee River Gorge