[2] In the segment in the state of Oklahoma, the highway closely corresponds to the old Chisholm Trail for cattle drives from Texas to railheads in Kansas in the 1860s and 1870s.

At this point, it is routed along Interstate 29 (I-29) and continues northward into Manitoba on Highway 75, which leads to Winnipeg.

Between the inception of the numbered highway system in 1926 through 1991, US 81's southern terminus was at the Mexican border in Laredo, Texas.

The route was shortened to its present length of 1,234 miles (1,986 km) in 1993, when the terminus was moved to Fort Worth.

The 1936 Official Map of the Highway System of Texas clearly shows the route labeled both as US 81 and SH 2.

In 1940 US 287 was extended south into Texas, and a 67-mile (108 km) stretch from Fort Worth northwest to Bowie was cosigned with US 81.

The summer 1941 Texas Highway Map shows this pairing, and the current southern terminus of US 81 is still cosigned with US 287.

By pure coincidence, the Chisholm Trail of the post-Civil-War decades roughly followed along the corridor of present-day US 81; the region was not opened for settlement until several years after the cattle drives were discontinued; cultural memory harkened exclusively for many years to Indian Meridian Highway until recognition of the old cattle trail grew in the late 1900s.

I-135 ends at I-70 but US 81 continues as a freeway to Minneapolis, then as an expressway passing through Concordia before exiting the state north of Belleville.

North of Norfolk, US 81 is a two-lane, undivided highway which passes through no towns before exiting the state in Cedar County.

US 81 enters South Dakota by a Missouri River crossing, via the Discovery Bridge at Yankton.

The two highways remain concurrent through the rest of the state, leaving South Dakota near New Effington.

It is paired with I-29 from the South Dakota border, passing through Fargo, to the north side of Grand Forks.

It parallels I-29, passing through the town of Grafton before joining North Dakota Highway 5 (ND 5) near Cavalier.

[5] The southern terminus, initially at Galveston,[6] was later moved to Laredo, where it would connect with a proposed extension to Mexico City (later built as part of the Pan-American Highway).

The portion through northern Kansas and Nebraska remains an important regional corridor and was proposed as a potential Interstate in the 1960s,[14] but by the late 1970s, the rest had been mostly replaced by I-35 and I-29 for non-local traffic.

[15] The American Association of State Highway and Transportation Officials approved a truncation in 1991, changing the southern terminus from Laredo to north of Fort Worth and removing long overlaps with and short sections parallel to I-35.