SR 50 begins as a 2-lane secondary highway in Hickman County at exit 148 on I-40 near Only as a continuation of Duck River Road.

The highway then passes south of Littlelot, where it has an intersection with SR 230 shortly before another bridge over the Duck River, an interchange with the Natchez Trace Parkway, and crossing into Maury County.

SR 50 then narrows to 2-lanes and has an intersection with Tom J Hitch Parkway before turning southeast and leaving Columbia, becoming New Lewisburg Highway.

The highway now passes through farmland and has an intersection with SR 373 in the Glendale community before having an interchange with I-65 at exit 37, shortly before crossing into Marshall County.

The highway then becomes N Ellington Parkway as it has an intersection with SR 417 just before splitting off from US 431/SR 106 onto Franklin Avenue to enter downtown.

US 431/SR 50 becomes Lewisburg Highway as it continues southeast through farmland to enter Fayetteville on the north side of town.

Turning northeast, it becomes Mulberry Avenue as it leaves downtown and comes to an intersection with US 64 Bypass and US 231/SR 10, where it becomes Winchester Highway.

SR 50 then winds its way through the countryside for the next few miles before crossing a bridge over the Elk River and entering Franklin County, passing just south of Tims Ford Dam.

This section of SR 50 between Lynchburg and Winchester is popular with area motorcyclists and sports car drivers due to its sinuousness.

SR 50 then becomes primary as it splits from US 41A/SR 16 as W Main Street to enter and pass through the neighboring town of Decherd as a 2-lane.