The current alignment begins at the junction of South Dakota Highway 34 at "Lee's Corner" east of Fort Thompson, and ends at the Iowa border near Richland, where it continues as Iowa Highway 3.

When it was formed in the 1920s, it traveled the entire length of southern South Dakota, from the Wyoming state line west of Edgemont, to the Iowa state line at Sioux City.

When U.S. Route 18 (US 18) was designated in the late 1920s, it replaced the SD 50 designation from the Wyoming state line at Ravinia (east of Lake Andes).

At US 77 (with which it had previously shared a concurrency to Sioux City), SD 50 was extended east to the Iowa state line.

It was routed west to Chamberlain, then assumed a segment of SD 47 (which had been realigned west) to its new northern terminus at SD 34 east of Fort Thompson.