From LaPlace, Louisiana, Mississippi, to Memphis, Tennessee, much of that portion of US 51 runs largely parallel or is concurrent with Interstate 55 (I-55).

The highway's northern terminus is between Hurley, Wisconsin, and Ironwood, Michigan, where it ends with a roundabout at US 2.

US 51 is routed through the states of Louisiana, Mississippi, Tennessee, Kentucky, Illinois, and Wisconsin.

In addition to singing about US 61 on his album Highway 61 Revisited, musician Bob Dylan also commemorated US 51, covering the folk song "Highway 51 Blues", earlier recorded by both Curtis Jones and Tommy McClennan, on his eponymous album Bob Dylan.

The North Mississippi Allstars also paid tribute to the highway in the title track of their album 51 Phantom.

In 2004, the six states that US 51 traverses banded together as the Explore Hwy 51 Coalition to help promote this "All-American Road".

US 51 enters Kentucky at Fulton, running concurrently with I-69 and continues northward through the towns of Clinton, Bardwell and Wickliffe to the Ohio River.

The route remains two lanes from Dongola to just before Assumption with the exception of a 10-mile (16 km) section between Centralia and I-64.

US 51 splits off from I-39/I-90 in South Beloit, Illinois, and continues northward through Janesville and Edgerton.

US 51 runs almost parallel to I-39/I-90 through the eastern portion of Madison, crosses the Interstate in DeForest, and finally rejoins I-39 again at Portage.

US 51 runs concurrently with I-39 until I-39's terminus in Wausau and continues on as a mixture of freeway and expressway until just north of the interchange with US 8.