US-281 passes within one mile (1.6 km) to the east of the Geographic center of the contiguous United States, which its connected to via K-191 (Kansas highway) (K-191).

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.

[4] In a July 10, 1946 resolution, a roughly 2.5 miles (4.0 km) section was realigned from US-160 southward, near Medicine Lodge, to eliminated several sharp curves.

[9] In a January 11, 1951 resolution, an approximately six miles (9.7 km) section of US-281 was realigned northwest of Sawyer, which eliminated a sharp turn and two railroad crossings.

[10] In a February 14, 1951 resolution, a roughly twelve miles (19 km) section of US-281 was realigned northwest of Kiowa to eliminate eight sharp curves.

[11] In a January 28, 1954 resolution, US-50S (modern US-50) was realigned between US-281 and Stafford to eliminate several sharp curves, which created a short overlap with US-281.

[14] In a December 22, 1958 resolution, a four miles (6.4 km) section of I-70 was planned along with a diamond interchange to connect to US-281.

[15] In another December 22, 1958 resolution, a short section of US-281 was realigned northwest of Portis to eliminate three sharp curves.

[22] On March 4, 2020, traffic was rerouted, from a four-way stop and temporary asphalt detour, onto the permanent concrete outer roads for the roundabout.

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