U.S. Route 64 Alternate (US 64 Alt) was established in 1979, replacing the old mainline US 64 through the town of Spring Hope.

U.S. Route 64 Alternate (US 64 Alt) was established in 1987, replacing the old mainline US 64 between the cities Rocky Mount and Tarboro.

U.S. Route 64 Alternate (US 64 Alt) was established in 1996, replacing the old mainline US 64 between the cities Princeville and Williamston.

Mainline US 64 is signed as both Bypass and Truck route, going south around Farmington, via Murray Drive.

was established in 1960, replacing the old mainline US-64 through downtown Muskogee, via Okmulgee Avenue and South Main Street.

U.S. Route 64 Business (US 64B) starts from US 64 and goes west into downtown Wynne, ending at Falls Boulevard (AR 1).

U.S. Route 64 Business (US 64B) was established in 1972, it starts from US 64 and goes west into downtown Parkin, ending at Church Street.

U.S. Route 64 Business (US 64 Bus) was established in 1971 when mainline US 64 was placed on new bypass south of Hayesville.

[22] In 2006, NCDOT submitted a request to officially make US 64E and US 64W through downtown Brevard, but was denied in the AASHTO Fall Meeting.

Continuing along Avery Avenue and Lenoir Road, it reconnects with mainline US 64, via Sanford Drive.

U.S. Route 64 Business (US 64 Bus) was established in 2020 when mainline US 64 was placed on a new freeway bypass south of Asheboro.

U.S. Route 64 Business (US 64 Bus) was established in 2005 when mainline US 64 was placed on new freeway bypass north of Pittsboro.

The business route continues along the former mainline alignment through the downtown area, via East and West Streets.

[25] In 1975, mainline US 64 was placed on new freeway bypass north of Wendell and Zebulon, extending the business route an additional 3 miles (4.8 km), from near Eagle Rock to north of Zebulon (via Gannon and Arendell Avenues); the former bypass through Lizard Lick became NC 97.

At the intersection with US 431, an overlap with US 231 ends as it joins US 64 Bypass onto a new road named Thornton Taylor Parkway.

After passing the Lincoln Medical Center, the road curves from the northeast to northwest as US 64 Bypass ends at US 64, while US 231 continues northward along Thornton Taylor Parkway towards Shelbyville Highway.

was established in 1999 as a new primary routing bypassing Manns Harbor and Manteo, while also providing direct access between Nags Head and the mainland.

The highway was created for access to an industrial park at the request of City of Wynne officials in 1985.

The roadway continues south under city maintenance as Martin Luther King Street.

Signage is not primary, US 64 Truck signs are typically located on the side of major junction changes indicating direction of route.

[2] U.S. Route 64 Alternate (US 64A) was established in 1952, it replaced the old mainline US 64 through downtown Siler City, via 3rd Street.

[25] U.S. Route 64 Alternate (US 64A) was established in 1954, it replaced the old mainline US 64 through downtown Columbia, via Main Street.

[25] U.S. Route 64 Business (US 64 Bus) was established in 1967, replacing the old mainline US 64 through downtown Enid, via Rock Island Boulevard, Grand Avenue and Owen K. Garriott Road.

However, this business loop designation lasted six months before being decommissioned in 1980; reason was because request to AASHTO was denied.

U.S. Route 64 Business (US 64 Bus) was established around 1965 when mainline US 64 was placed on new freeway bypassing north of Raleigh.

The business route began at the Western Boulevard interchange with US 64/US 1 and proceeded east into the downtown area, where it became Boylan Avenue.

At Boylan/South intersection, US 64 turns right onto South Street, while NC 31 continues on along Boylan Avenue to Central Prison.

Continuing along East Street, it turns right onto New Bern Avenue then meeting back with US 64 at the beltline.