SR 22 begins at a hybrid diamond–partial cloverleaf interchange on the concurrent I-82 / US 12 near Buena. The route heads south through farmland towards the town of Toppenish in Yakima County, which is also part of the Yakama Indian Reservation. While in Toppenish, the highway passes over double track belonging to BNSF Railway. On the south end of town, SR 22 intersects US 97, turning southeast as US 97 heads south. Traveling southeast, SR 22 passes through more farmland, passing the small census-designated place of Satus and an interchange with SR 223. The city of Mabton is located just north of the highway, and is accessible by turning onto SR 241. The highway leaves the reservation and turns southwest after passing the Sunnyside Wildlife Recreation Area, and crosses the Yakima–Benton county line, continuing through farmland until approaching the outskirts of Prosser, the county seat of Benton County. SR 22 serves as a bypass of Prosser, turning north until intersecting Wine Country Road on the east side of Prosser before turning back southwest on Wine Country Road and terminating at a folded diamond interchange, exit 82, on I–82.