U.S. Highway 52 (US 52) enters the state of Minnesota at the unincorporated community of Prosper, north of the town of Burr Oak, Iowa.

The route is marked north–south in Minnesota along its independent segment from the Iowa state line to downtown St. Paul.

US 52 is not signed along the length of its concurrency with Interstate 94 (I-94) from downtown St. Paul to the North Dakota state line at Moorhead and Fargo.

The roadway expands further to six lanes around Rochester, from the junction with US 63 to County Road 14 (CR 14), which is at the northern tip city.

The route enters Inver Grove Heights where it becomes the Lafayette Freeway north of Concord Boulevard.

After US 52 crosses the Mississippi River in downtown St. Paul, is intersects I-94 and follows I-94 to the North Dakota state line; US 52 is not signed along the length of this concurrency.

Progressing further, it took another left turn at Broadway Street before eventually curving to the northwest towards Robbinsdale, Crystal, Brooklyn Park and Osseo.

The Lafayette Bridge which takes the highway across the Mississippi River near downtown St. Paul was originally built in 1968 and was a "fracture critical" structure which was in need of replacement.

In November 2013, a diverging diamond interchange (DDI), the Elk Run interchange, was completed in New Haven Township, Olmsted County, between Oronoco and Pine Island, at a relocated CR 12; in addition, CR 31 was relocated, direct accesses to US 52 from 120th and 520th streets were closed, a frontage road system was created and roundabouts were constructed on surrounding roads; the project cost was $34.3 million.

Instead, it was decided that a moveable gate would be placed on Main blocking access to the at-grade intersection; the southbound exit ramp would be retained.

Pine Island and Goodhue County officials decried the design of the closure as "awkward", noting that during heavy snows, vehicles could go around the gate and still access US 52.

The officials called for an interchange or some other solution to restore access to US 52 from the north side of Pine Island, but no funding or junction design had been identified as of 2015.