The route begins at the Dale Gardner Veterans Memorial Bridge over the Mississippi River between Sabula and Savanna, Illinois.
After descending the bridge, the two routes turn to the south and travel along a narrow, 2+1⁄2-mile-long (4.0 km) causeway through the Mississippi backwaters.
The roadway gradually enters the Driftless Area, a region of the midwestern United States which escaped glaciation during the last glacial period.
Near the unincorporated community of Green Island, the highway passes through terrain where the elevation ranges from 600–800 feet (180–240 m) above sea level.
The Canadian Pacific Railway, which runs parallel to US 52 between Green Island and Bellevue,[5] in locations, lies 50 feet (15 m) below the road as the roadway follows the bluffs while the railroad tracks stay in the flat valley.
[7] North of St. Donatus, the highway travels 10 miles (16 km) and enters the Dubuque area.
It follows this north-south route through New Vienna, passing near the Field of Dreams filming site, until the northern terminus of Iowa 136 in Luxemberg.
After crossing the Turkey River, the highway rises nearly 300 feet (91 m) in elevation before descending again at Guttenberg.
It heads to the north-northeast for nine miles (14 km) to an intersection with Iowa 9 on the southwest side of Decorah.
Two miles (3.2 km) north of Burr Oak, US 52 crosses the state line into Minnesota.
During this time, Iowa 136, which previously ended at US 52 in Luxemburg, was truncated back to US 20 at Dyersville, but it was redesignated along this segment after US 52 returned to its old alignment.
Once reaching the proposed Southwest Arterial, US 52 would turn onto that new highway[15][16][17] and at its end, share an alignment with US 20.
[19][8] A new Mississippi River crossing, the Dale Gardner Veterans Memorial Bridge, opened on November 17, 2017.