On its route, I-29 passes through western portions of Sioux Falls, the state's largest city.

[1] I-229, the highway's lone auxiliary route in South Dakota, serves as a bypass around southern and eastern Sioux Falls.

[4] Average daily traffic volume on I-29 in South Dakota is relatively low by Interstate Highway standards.

I-29 crosses from Iowa into South Dakota at the Big Sioux River and enters the state in Union County.

Farther north of Elk Point, the route runs northwest until its interchange with SD 50 at exit 26.

Two miles (3.2 km) north of the Tea interchange, the Interstate enters Sioux Falls, the largest city in South Dakota.

Exit 81 serves Russell Street, which leads to the new Denny Sanford PREMIER Center and the Sioux Falls Arena.

At exit 83, I-29 intersects SD 38, also known as 60th Street North, which serves the Sioux Falls Regional Airport.

Just north of the Sioux Falls city limits at exits 84A and 84B, a cloverleaf interchange, I-29 reaches I-90, the only other two-digit Interstate in South Dakota.

Two miles (3.2 km) north of the interchange with I-90, the highway reaches exit 86, which serves Renner and Crooks, the two northernmost suburbs of Sioux Falls.

The highway serves the EROS Data Center and United States Geological Survey near Baltic.

The highway then continues north and intersects the northern terminus of SD 115 west of Dell Rapids.

Just five miles (8.0 km) north of here, the route shares an interchange with SD 32, a highway that serves nearby Flandreau, South Dakota.

[6] I-29 intersects US 81 at exit 180, just northeast of Watertown, and the two routes become concurrent all the way to Manvel, North Dakota.

At the state border is a parclo interchange entirely on the North Dakota side serving the casino–hotel.

The entire freeway from Kansas City, Missouri, to the Canadian border was then built and signed as I-29.

On April 1, 1962, some of the northbound directional spans collapsed into the Big Sioux River at the Iowa state line as a result of flooding and bridge scour.