The highway runs parallel to the state's southern border with Nebraska, and at one point, near Fairfax, US 18 comes within one mile to the Nebraska border.

US 18 enters South Dakota west of Edgemont.

It passes through Hot Springs, the Pine Ridge Indian Reservation, the Rosebud Indian Reservation, Winner, and Gregory, before crossing the Missouri River near Pickstown over Fort Randall Dam.

East of the Missouri River, US 18 passes through (or near) Lake Andes and Tripp before a brief concurrency with Interstate 29 (I-29) near Worthing.

East of I-29, US 18 passes through Canton before crossing the Big Sioux River into Iowa.