It enters the state from Oklahoma while overlapped with US 287, but splits at Lamar to follow its own route through the Eastern Plains to Nebraska.

Communities along the route include Bristol, Sheridan Lake, Cheyenne Wells, Burlington, Wray, Holyoke, and Julesburg.

30S (Dallas-Canadian-Denver Highway) to the Kansas state line in the direction of Guymon, Oklahoma.

[5][6] (The connection in Kansas would become K-51 several years later,[7] but the rest of the road to US 64 west of Guymon did not become Oklahoma State Highway 95 until 1953–1954.

At the same time, a new State Highway 166 (SH 166) was created, paralleling the Union Pacific Railroad's Overland Route from US 138 west of Julesburg northwesterly to the Nebraska line (where it connected with Nebraska Highway 27).

Otherwise, paving was begun in 1941–1942 between Holyoke and Julesburg, and was completed north of Cheyenne Wells in 1957–1958.

In Colorado it followed US 287 from Oklahoma to Kit Carson, US 40 east to Cheyenne Wells, SH 51 to Julesburg, and former SH 166 (paved in 1959–1960) was returned to the state highway system for the final bit into Nebraska.

The remaining independent section of SH 51 was paved over the next few years and completed in 1963–1964, at which time US 385 was moved off US 287 north of Lamar.