U.S. Route 81 (US-81) is a north–south U.S. highway running through the central United States' Great Plains region, from Fort Worth, Texas to the U.S.–Canadian border at Pembina, North Dakota.

US-81 crosses the Red River from Texas south of Terral, passing through several Oklahoma cities, such as Chickasha, El Reno, Kingfisher, and Enid, before entering Kansas north of Renfrow.

The route of US-81 was originally served by the Chisholm Trail, which was used to drive cattle from Texas to Abilene, Kansas.

North of Ryan, the highway begins paralleling Beaver Creek, a tributary of the Red River, and bypasses Sugden to the east.

The highway curves northeast to bisect Addington before returning to a due north course as it enters Stephens County.

Upon leaving Comanche, US-81 curves northwest before resuming its course to the north, passing through the gap between Sunray and Empire City.

Further north, an interchange offers travelers an opportunity to join the Duncan Bypass, which parallels US-81 to the west.

At this same interchange, eastbound SH-7 toward Davis can be accessed, while westbound SH-7 forms a concurrency with the Duncan Bypass proceeding west of 16th Street.

US-81 continues due north, passing from Union City into the Canadian County seat, El Reno, where it comes to an interchange with I-40/US-270.

US-81 and I-40 Business turn northwest, heading into downtown El Reno along Rock Island Boulevard.

I-40 Business turns west onto Sunset Drive, while US-81 continues due north along Choctaw out of town.

As they approach the southern limits of the county seat, Kingfisher, they curve back to a due north course.

[6] From Waukomis, the highway proceeds north to Vance Air Force Base, which it passes just east of.

Still accompanied by US-60 and US-64, the route heads north from the county line for approximately 5 miles (8.0 km) before coming to a T intersection.

After four miles (6.4 km), the highways come to the town of Pond Creek; here US-60 splits off toward Lamont, while US-81 heads north.

The route then exits the state of Oklahoma, passing into Sumner County, Kansas, heading north toward Caldwell.

[4] Prior to the establishment of the U.S. Highway System, US-81's general corridor through Oklahoma was the site of the Chisholm Trail, a principal route used on cattle drives from Texas to stockyards in Kansas.