It begins at the South Dakota state line south of the small town of Reeder and ends at ND 23 west of New Town and north of Mandaree.

The highway widely parallels US 85, running about fifteen miles east of it.

It then heads north, joining with Highway 21 south of New England.

ND 22 continues north to meet Highway 200 just south of the city of Killdeer.

The route continues just west of Mandaree, then meets Highway 73, and finally ends at Highway 23 in an unpopulated area west of Lake Sakakawea and New Town in McKenzie County.