It runs from south to north for a length of 12 miles (19 km).

It has a southern terminus at Nebraska Highway 89 west of Stamford.

Nebraska Highway 46 begins at Nebraska Highway 89 west of Stamford.

It goes north and meets U.S. Highway 136 in Oxford.

After a brief northwesterly section, the highway turns north at the Furnas County/Harlan County border and ends when it meets U.S. 6 and U.S. 34 north of Oxford.