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. A 229.28-mile (368.99 km) segment of the highway lies within the state of Oklahoma. 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.

Chickasha is a city in and the county seat of Grady County, Oklahoma, United States. The population was 16,051 at the 2020 census, a 0.1% increase from 2010. The city is named for and strongly connected to Native American heritage, as "Chickasha" (Chikashsha) is the Choctaw word for Chickasaw. Chickasha is home to the University of Science and Arts of Oklahoma.