SD 22 begins at an intersection with the northern terminus of 1st Street and the southern terminus of Mustang Avenue in the north-central part of Hazel, within the northwestern part of Hamlin County. Here, the roadway continues to the west as Hamlin County Road 181/181st Street. SD 22 travels to the east. Just east of William Street, it crosses over some railroad tracks of BNSF Railway. Just east of 444th Avenue, it travels just south of the Baxter Slough State Public Shooting Area. East of 449th Avenue, it travels through Thomas. the highway then curves to the southeast to travel around the southwestern part of Clear Lake. Just east of 451st Avenue, it curves to the east-northeast. Just west of 452nd Avenue, it curves to the east-southeast. East of 454th Avenue, it travels through the Five Ponds area. It then intersects US 81. The two highways travel concurrently to the south-southeast. Here, the roadway continues to the east as 181st Street. At 183rd Street, SD 22 splits off to the east-northeast. Just east of 458th Avenue, it crosses over the Big Sioux River and then travels just north of Castlewood. An intersection with the northern terminus of 2nd Avenue leads to Castlewood. An intersection with 459th Avenue and the northern terminus of 4th Avenue, which is signed as a "city truck route", leads to a city park. East of 461st Avenue, it crosses over Stray Horse Creek and then curves to the north-northeast. Almost immediately, it curves back to the east. East of 465th Avenue, it has an interchange with Interstate 29 (I-29). While traveling under the Interstate highway, it enters the west-central part of Deuel County.