It enters Iowa from Nebraska, concurrent with Interstate 129 (I-129) and US 75, crossing the Missouri River at Sioux City.

About three miles (4.8 km) further east, at Ida Avenue (County Route D22, or CR D22), the newest four-lane stretch (except for a short expressway segment just south of Holstein that is briefly concurrent with US 59)[2] starts and goes to about one mile (1.6 km) west of an interchange with US 71 and Iowa Highway 471 (Iowa 471), just north of Early.

[3] From this point until an interchange with Iowa 4 northwest of Rockwell City is the second newest section of four-lane, which opened in November 2012.

East of Fort Dodge, US 20 overlaps with Iowa 17 for 4.5 miles (7.2 km), ending at Webster City.

Beginning at the interchange with US 65 is a section of four-lane freeway which, when completed, shaved nearly 16 miles (26 km) off US 20's length.

On the southeast side of Waterloo, I-380 joins US 20/Iowa 27 for six miles (9.7 km) before exiting with Iowa 27 south toward Cedar Rapids.

Approximately 21 miles (34 km) between Independence and Manchester, the highway goes over a terminal moraine and enters the Driftless Area, a region it will not exit until reaching Stockton, Illinois.

At Delaware, US 20 changes from a freeway to an expressway with at-grade intersections; however, there are many interchanges where US 20 meets major roads, mostly at the villages and towns along US 20's route.

US 20 serves Earlville, Dyersville (where US 52 joins the route and passing near the Field of Dreams filming site), Farley, Epworth, and Peosta before entering Dubuque.

On the western edge of Dubuque, an interchange onto the Southwest Arterial routes US 52 around the southern outskirts of the city, connecting to US 61 and US 151.

Near the river, Locust Street (Iowa 946) connects US 20 with US 61 and US 151, which have entered the city from the south as an expressway and continue northward as a freeway.

From Alden to Webster City, twenty-five miles [40 km], with the exception of a stage station where horses were changed, there was nothing but the virgin prairie.

From Webster City to Fort Dodge, twenty miles [32 km], there was no house but that of the enterprising muskrat.

[...] Here was a route from Cedar Falls to Sioux City, two hundred miles [320 km] long in a straight line, that typified the highest stage of development west of the railroads.

By the end of the 1980s, the four-lane portions of US 20 ran from Coalville (near Fort Dodge) to I-35 and from Waterloo to Dubuque.

The new expressway carried the three routes beneath the approach to the Julien Dubuque Bridge, making a direct intersection impossible.