The Minnesota Department of Transportation has a long-term goal of making US 52 a freeway with limited-access interchanges between St. Paul and I-90 south of Rochester.

The portion of the highway between Inver Grove Heights and Pine Island is built to expressway standards.

US 52 roughly parallels the Mississippi River for the rest of its path through Iowa to Dyersville, where it intersects and joins US 20 and turns eastward towards Dubuque.

West of Dubuque, US 52 merges south onto the Southwest Arterial, a four-lane expressway directing traffic around the southern edge of the city.

All three routes travel northbound (even US 52, which is signed as southbound) as an expressway, until US 52 departs in Key West to remain close to the Mississippi River.

After passing through a hilly and scenic region, including the small river city of Bellevue, the highway turns to an east–west orientation near Sabula at the junction of Iowa 64 and the northern terminus of US 67.

In Sabula, the highway becomes a wrong-way road; northbound traffic travels south, and vice versa, from Sabula to the Dale Gardner Veterans Memorial Bridge, where US 52 crosses over the Mississippi River into Illinois.

[2] After the completion of the Southwest Arterial in 2020, a similar change took place as US 52 was once again removed from the Iowa Highway 3 alignment and again routed from Luxemburg to Dyersville to Dubuque, then onto the Southwest Arterial, to US 61/US 151, finally reaching its former routing at Key West.

It joins with US 45 through Kankakee, thereafter running concurrently with US 24, east of Watseka to the Indiana state line.

It runs along Central Parkway and Central Avenue through downtown and then skirts the Cincinnati riverfront along Mehring Way past Paycor Stadium (formerly Paul Brown Stadium), Great American Ball Park, and Heritage Bank Center (formerly U.S. Bank Arena), onto Pete Rose Way and Riverside Drive.

The section between I-275 and New Richmond was modernized in the 1960s; parts of the old route run parallel to the newer highway.

This portion of US 52, along the Ohio between Cincinnati and Huntington, is the only part where it falls in geographical sequence, south of US 50 and north of US 60.

US 52 serves western and southern portions of West Virginia, running from Huntington to Bluefield.

The highway is undergoing a major expansion project which began in 2007 and at current funding levels is likely to take many years to finish.

It enters southwestern Virginia near Bluefield and passes through Wytheville and Hillsville before leaving the state south of Cana.

The segment from northern Winston-Salem to just south of Mount Airy is expected to form part of the I-74 corridor through North Carolina.

South of the Triad area, after splitting from I-85 in Salisbury, US 52 is typically a two-lane route linking some of the state's smaller cities and towns.

From Darlington southward it is a multilane highway and freeway, passing through Florence, Lake City, Kingstree, Moncks Corner and North Charleston before US 52's terminus at the intersection of Meeting and Line Streets in Charleston.

On April 10, 2015, a rockslide dropped a boulder the size of a house onto the westbound lanes of US 52 in Lawrence County just east of the bridge over the Ohio River to Ashland, Kentucky, leading to closures and detours while two days of cleanup took place.

[3] Established in 1926, US 121 traversed from Lexington, North Carolina, to Max Meadows, Virginia, estimated to be 107 miles (172 km).