US 45W begins in Madison County, concurrent with unsigned SR 5, in Three way at an interchange between US 45 and US 45E. The highway goes as a 4-lane divided highway to cross into Gibson County and enter Humboldt, where they come to an intersection with unsigned SR 366. Here, SR 5 follows US 45W Business through while US 45W bypasses downtown to the west and north along SR 366, where it has intersections SR 152 and US 70A/US 79/SR 76. US 45W and SR 5 then rejoin at an intersection with US 70A Bypass/US 79 Bypass, and they leave Humboldt head north through farmland. US 45W/SR 5 then pass through Fruitland, where it has an intersection with SR 420 before passing through rural areas. It then enters Trenton at an intersection with SR 457 and SR 367, where US 45W/SR 5 turn right to follow a 2-lane bypass of downtown on the eastern side. The highway becomes concurrent with SR 54 and an intersection with SR 186 in a business district before having an intersection with SR 77 and SR 104, where it becomes concurrent with SR 77, in a more rural part of town. SR 54 then splits off before the highway curves to the west to have another intersection with SR 367. US 45W/SR 5/SR 77 then widen to a 4-lane divided highway to curve back northward and leave Trenton. They wind their way north through farmland to pass through Dyer, where it bypasses the town on its west side, to have an interchange with SR 185, where SR 77 splits off and goes west. US 45W/SR 5 continue north to pass through Rutherford, where it bypasses the town on its west side, and has an interchange with SR 105. US 45W/SR 5 then narrows to 2-lanes as it has an intersection with its former alignment just before entering Kenton and crossing into Obion County. US 45W/SR 5 have a short concurrency with SR 89 before leaving Kenton and continuing north. The highway passes through a wooded area to cross a bridge over the Obion River before passing through farmland to become concurrent with SR 21. They then have an intersection with SR 216 just west of Rives before continuing north to enter Union City and come to an intersection with SR 431/SR 184, where US 45W splits from SR 5 and turns right onto SR 431/SR 184. US 45W/SR 431/SR 184 goes east through a business district as a 4-lane undivided highway before entering neighborhoods before US 45W/SR 184 split off from SR 431 and follow S Miles Avenue. They then make a right onto Nailling Drive to pass through more rural and suburban areas before coming to an interchange between SR 22 and SR 214, where SR 184 ends and US 45W turns north along SR 22. They immediately come to an interchange with US 51/SR 3, where US 45W splits from SR 22 and heads northeast along US 51/SR 3 as a 4-lane freeway. They then have another interchange with SR 214 to enter South Fulton before arriving at an interchange with US 45E/SR 215, where US 45W and US 45E merge to form mainline US 45.
