Its southern terminus is at Nebraska Highway 23 east of Eustis.

It goes north through farmland and meets Interstate 80 shortly before Cozad.

In Cozad, it meets U.S. Highway 30 and goes on a 13-mile (21 km) concurrency eastward to Lexington.

At Lexington, it turns north into rural prairie areas and meets Nebraska Highway 40 in Oconto.

[1][2] The original version of Nebraska Highway 21 went south from Lexington and turned east to go through Beaver City and Alma.