The original pavement on US 52 between Dubuque and Luxemburg was in such poor condition that in 1964, the Iowa State Highway Commission temporarily rerouted US 52.

[3] Once comprehensive repairs were made to the roadway by 1968, the mainline designation was restored to the routing.

The business route was established at that time but was poorly signed for many years until 1999 when an effort to improve signage was completed.

U.S. Route 52A was established in 1953, replacing the old mainline US 52 through downtown Mount Airy, via Main Street.

[9] U.S. Route 52A was established in 1949, replacing the old mainline US 52 through Pilot Mountain, via Main Street.

[7] U.S. Route 52 Business was established in 1960, a renumbering of US 52A through Pilot Mountain, via Main Street.

It was decommissioned in 1964 when the Pilot Mountain Parkway was opened, taking US 52 onto a new alignment west of town.

It begins concurrent with US 301 (Freedom Boulevard, which is signed as a US 301 truck route), but branches off on its own.

[26] One section of the route, Morrison Drive near Jackson Street, will flood regularly during a spring tide.

The southern terminus is near the historic wharves of Charleston, including Adgers Wharf, which is now the site of a playground.

The current Customs House that was built around the time of the Civil War is on this route.

[28] When Morrison Drive was constructed, there was still one private terminal operating near the southern terminus, the Clydeline Steamship Company.