Running for nearly 100 miles (160 km), US 18 has a speed limit of 70 mph (110 km/h) with the exception of its ending terminus at Orin and the portion throughout Lusk.

[citation needed] The Oyate Trail is one of the names given (in the late 1990s) to the section of US 18 traveling across South Dakota from I-29 east of Vermillion to Maverick Junction.

[6] Named in an attempt to encourage more tourism traffic through the lands of various Indigenous peoples in southern South Dakota, it passes through or near the Yankton Sioux, Rosebud, and Pine Ridge Indian reservations, crossing the James River Valley, the Missouri River near Fort Randall Dam, portions of Pine Ridge, and the High Plains of South Dakota, connecting the urban areas of the middle Missouri River with the Black Hills.

[citation needed] Towns along the road include Gregory, Winner, Olivet, Mission, Martin, Batesland, and Pine Ridge.

After passing through West Union, it turns northeast and joins US 52 at Postville, then leaving US 52 about seven miles (11 km) east of Monona before crossing the Mississippi River into Wisconsin via the Marquette–Joliet Bridge in the city of Marquette.

[citation needed] Upon entry into Wisconsin at Prairie du Chien, US 18 is the terminus for State Trunk Highway 60 (WIS 60).

US 18 follows US 12 south of Madison and passes through or around Cambridge, Jefferson, and Waukesha before terminating in Milwaukee at the junction of East Michigan Street and Lincoln Memorial Drive in downtown.