Its western terminus is at Nebraska Highway 70 south of Ord.

Nebraska Highway 22 begins at Nebraska Highway 70 south of Ord in rural Valley County, heading east into farmland.

At North Loup, NE 22 meets Nebraska Highway 11 and they are paired together for 2 miles (3.2 km).

NE 22 then goes east on an alignment which parallels the Loup River on its north side.

It passes through Genoa and Monroe before ending at U.S. Highway 81 near Columbus.