[1] The route passes through several cities and towns, including Fort Smith, Clarksville, Russellville, Conway, Searcy, and West Memphis.

[3] US 64 crosses the Arkansas River again near the American Doughboy Monument as it enters Van Buren on Broadway.

US 64 continues through mountainous Franklin County, intersecting the Pig Trail Scenic Byway in Ozark.

In Faulkner County, it briefly converges with US 65B through Conway heading south before diverging from US 65B and I-40 by turning east onto Oak Street.

The highway next approaches Vilonia, following a southerly bypass around the city that opened in October 2011[8] (replacing its former alignment along Vilonia's Main Street) and rejoining its prior alignment west of the White County line and continuing to El Paso, where it intersects Arkansas Highway 5.

US 64 runs along this divided highway past McRae, Garner, and Searcy, where its original route took it north along Main Street, then east along Race Avenue.

US 64 continues south to West Memphis, where its former route entered the city from the north via Missouri Street, turning east (diverging from US 63 while converging with US 70 & 79) onto Broadway.

When the United States Army began constructing the Memphis to Little Rock Road on January 31, 1824, it followed a historic trail through the region.

This stretch of road is about 0.65 miles (1.05 km) long and 18 feet (5.5 m) wide, carrying two lanes of traffic with no shoulder.

The bridge was built in 1933–1934 by Fred Luttjohann, and served as a major crossing point and transportation route until the construction of Interstate 40 (I-40) to the north.

It is about 0.5 miles (0.80 km) in length, following an arced route, and is covered in a bituminous that has in places deteriorated into gravel.

Now a portion of Canal Road, it consists of a 0.5-mile (0.80 km) section of concrete pavement, extending southward from the current alignment of US 64 near the center of Menifee.

Built in 1931 by the Zeigler Construction Company, it is the longest intact portion of the highway's original alignment in Conway County.