It is a mostly rural route, also serving the towns of Clinton, Arlington, Bardwell and Wickliffe.

It also carries part of the Great River Road near the northern end of its route in Kentucky.

US 51 mainly runs through the Jackson Purchase region of Kentucky, spanning the four westernmost counties in Kentucky, beginning with a four-lane section crossing the state line, which begins a concurrency with the I-69.

US 60 joins in on the overlap just before crossing the Ohio River into Alexander County, Illinois just south of Cairo.

Portions of US 51/US 62 in Carlisle and Ballard counties are part of the Great River Road National Scenic Byway.