The entirety of the route is in Nebraska's southern tier of counties.

It then passes through Ragan and Campbell and meets US 281 in northern Webster County.

It overlaps US 281 for 4 miles (6.4 km) and separates south of Blue Hill.

It goes east through Daykin and is briefly concurrent with Nebraska Highway 15 for one mile (1.6 km).

At Table Rock, it intersects NE 65 and continues eastward through Humboldt until it ends at U.S. Highway 75 near Dawson.