US 12 enters South Dakota from North Dakota as a rural two-lane highway about 10 miles (16 km) west-northwest of Lemmon before entering the Standing Rock Indian Reservation.

At Walker, US 12 heads southeast for 37 miles (60 km), where it crosses the Missouri River at Mobridge, exiting the reservation.

After leaving US 83, it turns due east and spends about 80 miles (130 km) as a rural two-lane highway again.

East of Waubay it becomes again an at-grade expressway until it meets with I-29 near Summit.

The speed limit from Aberdeen to I-29 is 70 mph (110 km/h) except through the communities of Groton, Webster, and Waubay.