The highway largely lies within 10 miles (16 km) of the South Dakota border its entire length.

It goes northeast out of Valentine through the Fort Niobrara National Wildlife Refuge before turning east.

It continues eastward through the tribal lands of the Ponca Tribe of Nebraska and around the edge of Niobrara State Park.

It continues on the same line eastward, intersecting U.S. Highway 81 in the process, then turns southeastward near Wynot.

It meets Nebraska Highway 15 and the two routes are paired together through Obert and Maskell before NE 15 turns north to go toward Vermillion, South Dakota.