The westernmost segment of SD 42 begins at a junction with U.S. Route 281 (US 281) and travels east through open farmland.

About six miles (9.7 km) farther east, SD 42 bends slightly to the south and crosses the James River.

Here, it curves to the northeast and crosses another branch of the BNSF Railway[3] before meeting the eastern terminus of SD 262.

The central segment of SD 42 ends at Ellis Road near the Sioux Falls city limits.

The highway passes through the unincorporated community of Rowena before curving due south and crossing the Iowa state line.