U.S. Route 51 is a north–south United States highway that runs for 1,286 miles (2,070 km) from the western suburbs of New Orleans, Louisiana to within 100 feet (30 m) of the Wisconsin-Michigan border. Much of the highway in Illinois and southern Wisconsin runs parallel to or overlaps Interstate 39. The highway's northern terminus is between Hurley, Wisconsin and Ironwood, Michigan, where it ends with a T interchange at U.S. Route 2. Its southern terminus is Laplace, Louisiana, ending at U.S. Highway 61.

In addition to singing about U.S. Highway 61 on his album Highway 61 Revisited, musician Bob Dylan also commemorated Highway 51, covering Curtis Jones' folk song "Highway 51 Blues" 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 Memphis, Tennessee, all of U.S. 51 south of South Parkway East was renamed from Bellevue Boulevard to Elvis Presley Boulevard. Graceland sits on this highway, in the subdivision of Whitehaven.

In 2004, the six states that Highway 51 traverses banded together as the Explore Hwy 51 Coalition to help promote this "All-American Road". The group now offers visitor information for traveling the length of the road.

U.S. 51 crosses the Mississippi/Louisiana border a few miles north of Kentwood and continues to parallel Interstate 55 until just below its interchanges with LA 3234 and U.S. 190 it joins I-55 just south of Hammond at Exit 28. From Hammond, the two highways, cosigned, cross the swamps between Ponchatoula and Laplace on viaducts to Interstate 10, where I-55 ends. The old highway is located to the east of the interstate and is still used for local traffic. U.S. 51 continues southwestward into Laplace where it meets its end at U.S. 61 (Airline Highway). In the 1930s, this highway was called Jefferson Davis Highway.

Before the construction of I-55, U.S. 51 was routed along what is now U.S. 51 Business between Hammond and Ponchatoula. U.S. 51 Business ends at the joined I-55/U.S. 51 south of Ponchatoula. From this point southward, while U.S. 51 is joined with I-55, the former routing of U.S. 51 lies at ground level just to the east of I-55/U.S. 51 and carries no designation. While the southern terminus of U.S. 51 is in Laplace at U.S. 61, it was once co-signed with U.S. 61 into downtown New Orleans. However, it was originally slated to head toward New Orleans along the south shore of Lake Pontchartrain via the New Orleans-Hammond Highway (old LA 33), which was never completed.

U.S. 51 enters the Magnolia State from Tennessee at Southaven and parallels Interstate 55 to the east for much of its length, except for the section between the Tennessee line and Grenada, where it parallels the highway to the west. From Memphis, U.S. 51 passes through Senatobia, Batesville, Grenada, Winona and Canton before reaching Jackson.

At the Jackson-Ridgeland line, U.S. 51 overlaps I-55 from Exit 103 (County Line Road) to Exit 96A (Pearl Street) downtown. The split is only temporary as the highway traverses Pearl, Pascagoula and State streets and meets I-55 again at Exit 93 (Interstate 20/I-55/State Street interchange). The Natchez Trace parkway is crossed near Clinton. The Natchez Trace Parkway is a 444 mile (715 km) long parkway, in the form of a limited-access two-lane road, in the southeastern United States. The southern end of the route is in Natchez, Mississippi, at an intersection with Liberty Road; the northern end is northeast of Fairview, Tennessee, in the suburban community of Pasquo, Tennessee, at an intersection with Tennessee 100. The road links the cities of Natchez, Mississippi, and Nashville, Tennessee, via Jackson and Tupelo, Mississippi, and Florence in northwestern Alabama.

The two highways run together until Exit 72 (North Crystal Springs). The highway then parallels the interstate through Hazlehurst, Brookhaven and McComb until it reaches the Louisiana border.

The Mississippi section of U.S. 51 is defined at Mississippi Code Annotated § 65-3-3.

US 51 travels through Memphis and up to the Kentucky border in the Mississippi valley. It is planned to become or be bypassed by Interstate 69 through Tennessee.

U.S 51 enters Kentucky at Fulton, and continues north through the towns of Clinton, Bardwell and Wickliffe to the Ohio River, where it is multiplexed with U.S highways 60 and 62 over the Ohio.

U.S Highway 51 enters Illinois from Wisconsin in a concurrency with Interstates 90 and 39. The concurrency with Interstate 90 is for 17 miles. There is a toll plaza on this stretch. It costs $1.90 for cars and 95 cents for those with I-Pass transponders. The highway makes a brief 3 mile concurrency with U.S. Highway 20 then heads south in a concurrency with Interstate 39 to Normal. At Normal, the highway makes a concurrency with Interstate 55 and Interstate 74, bypassing Normal and Bloomington. South of Bloomington, the highway is an expressway until Decatur, where it makes a concurrency with Interstate 72, bypassing Decatur. The highway is an expressway from south of Decatur until Assumption where it becomes a 2 lane road for most of the way to Interstate 57, with the exception of 10 miles between Centralia and Interstate 64. There is a concurrency with Interstate 57 for 23 miles. Passing through Carbondale, a section of the highway to the north of the main campus of Southern Illinois University is locally referred to as "The Strip." The highway then passes through Cairo before crossing the Cairo Ohio River Bridge concurrently with U.S. Highway 60 and U.S. Highway 62.

U.S. Highway 51 has intersections and concurrencies with Interstate 90, Interstate 39, Interstate 55, Interstate 74, Interstate 72, Interstate 70, Interstate 64, and Interstate 57.

In the state of Wisconsin, U.S. 51 enters from Illinois at Beloit. U.S. 51 splits off from Interstate 39 in Beloit and continues north through Janesville and Edgerton. In Edgerton, U.S. 51 rejoins Interstate 39 and Interstate 90 for three and a half miles before splitting off towards Stoughton and McFarland. U.S. 51 runs almost parallel to Interstates 39 and 90 through the eastern portion of Madison, crosses the interstate in DeForest, and finally rejoins the interstate at Portage. U.S. 51 runs concurrently with Interstate 39 until I-39's terminus in Wausau and continues on as a freeway until Merrill and then as a divided highway until just north of the intersection with U.S. Route 8. From there through Hazelhurst, U.S. 51 is a two-lane road with sporadic three-lane sections (which were recently constructed in 2008). U.S. 51 expands to four lanes with a central fifth turn lane from Hazelhurst to Arbor Vitae; north of Arbor Vitae it returns to two lanes and continues to its northern terminus in Hurley where it junctions with US 2.