The southern eastern terminus of US 281 is in Brownsville, Texas, just short of the Mexican border ending on Bus.

US 281, beginning at the west, or the lower Rio Grande Valley, at an intersection with Business US 77 and SH 48 about two miles (3.2 km) from the Mexico border.

At the east, or Upper Rio Grande Valley, turning north from Hidalgo, travelling through Las Milpas, Pharr, Edinburg, and many small towns while also having a Border Patrol checkpoint in Brooks County south of Falfurrias, Texas.

North of San Antonio, US 281 continues through central and north-central Texas, passing through many towns, including Stephenville, Mineral Wells and Jacksboro before reaching Wichita Falls, where the highway begins a concurrency with I-44 north across the Red River into Oklahoma.

US 281 enters the state of Oklahoma at the Red River bridge north of Burkburnett, Texas on a route concurrent with I-44 starting in Wichita Falls.

About six miles (9.7 km) north of the Red River, US 281 leaves I-44 at Randlett and follows a two-lane roadway parallel to the newer I-44, which becomes the Wichita Falls–Lawton section of the H.E.

Through the Lawton/Fort Sill metropolitan area, US 281 again overlaps a toll-free section of I-44, while the former US 281 alignment through the city of Lawton is designated as Business US 281 between I-44 exits 34 and 39B.

About two miles (3.2 km) north of its junction with I-40 near Hinton, US 281 crosses a 1930s-vintage 38-span steel pony truss bridge over the South Canadian River that served traffic of the former east–west US 66 before that highway was superseded by I-40 in the 1960s.

A four-mile (6.4 km) section of US 281's paving from north of I-40 to a point south of Geary is the original 18-foot (5.5 m) concrete surface of US 66.

Through central and northern Oklahoma, US 281 then proceeds through the cities of Geary, Watonga, Seiling, Waynoka and Alva.

Passing largely through sparsely populated areas of central Kansas, US 281 enters the state at Hardtner in Barber County and passes through Medicine Lodge, Pratt, St. John and Great Bend, the only city along the route in Kansas which has more than 7,000 people.

The last stretches of the highway overlaid with bricks, through downtown Pratt and Hoisington, were recently resurfaced with concrete.

US 281 continues north of Grand Island to St. Libory as American Legion Memorial Highway.

From there northward, US 281 is a two-lane undivided highway passing mostly through unpopulated areas, with the exception of the regional trade center O'Neill, where it junctions US 20 and US 275.

A bypass was built that travels on the west side of Aberdeen, and the US 281 designation was moved onto that new roadway.

Recently, US 281 was rebuilt near Minnewaukan, North Dakota to accommodate flooding close to the city.

[citation needed] US 281 between Grand Island and St. Paul in Nebraska is planned to be a four-lane expressway for its entire length.

[citation needed] The northwestern terminus of U.S. Highway 281 Bypass is directly adjacent to Brit Spaugh Park in Great Bend.