U.S. Route 20 in Iowa is a major east–west artery which runs across the state, separating the northern third of Iowa from the southern two-thirds. It enters Iowa from Nebraska, concurrent with Interstate 129 and U.S Route 75, crossing the Missouri River at Sioux City. US 20 runs in a more-or-less straight line across Iowa, paralleling 42° 27' N. It leaves Iowa in Dubuque by crossing the Mississippi River into Illinois. The state of Iowa is in the process of upgrading US 20 into a four-lane, limited-access highway for its entire length in Iowa.

U.S. Route 20 enters Iowa concurrent with Interstate 129 and U.S. Route 75 on a freeway which bypasses Sioux City to the south and east. Immediately after crossing the Missouri River into Iowa, Interstate 129 ends and US 20/US 75 intersect Interstate 29 and US 75 Business. On the east side of Sioux City at Gordon Drive, US 20 exits the US 75 freeway, which continues towards Le Mars.

East of Sioux City, U.S. Route 20 continues as an expressway until Moville. From there, it is a rural, two-lane highway with only a short expressway segment just south of Holstein, which is briefly concurrent with U.S. Route 59. From US 59, it is nearly 70 miles (110 km) until US 20 has another four-lane segment. On this two-lane segment, US 20 passes through the towns of Early and Sac City, and overlaps U.S. Route 71 for 3.6 miles (5.8 km) beginning just north of Early.

As of December 2010, the newest section of U.S. Route 20 was in operation, starting just northwest of Rockwell City, being concurrent with Iowa Highway 4 for a short while, and extending to the former beginning of the four-lane expressway northeast of Moorland. This continues until just south of Highview, when it becomes a full interstate-standard freeway. The freeway runs south of Fort Dodge where it has interchanges with U.S. Route 169 and Webster County Route P59. East of Fort Dodge, US 20 overlaps with Iowa Highway 17 for 4.5 miles (7.2 km), ending at Webster City. Near Williams, US 20 intersects Interstate 35, beginning the newest section of four-lane freeway, which shaved nearly 16 miles (26 km) off of US 20's length. Prior to 2003, US joined U.S. Route 65 north through Iowa Falls and then east towards Ackley and Parkersburg before heading south again to the freeway with Iowa Highway 14. The bridge crossing the Iowa River near Owasa is a launched steel I-girder bridge, the first of its kind in the United States. The bridge was designed to cross the old-growth woodland of the Iowa River valley with minimal impact.

U.S. Route 20 continues east towards Cedar Falls where it overlapped by Iowa Highway 58 for just over 1 mile (1.6 km). The western junction of Iowa 58 (Hudson Road) connects traffic to the University of Northern Iowa while the eastern junction of Iowa 58 is also the western junction of Iowa Highway 27, the Avenue of the Saints. Another mile east, in Waterloo, US 20 intersects U.S. Route 63 (Sergeant Road). On the southeast side of Waterloo, Interstate 380 joins US 20/IA 27 for 6 miles (9.7 km) before exiting with Iowa 27 south towards Cedar Rapids.

U.S. 20 continues as a freeway east of Waterloo. It intersects Iowa Highway 150 at Independence and Iowa Highway 13 at Manchester, as well as junctioning a number of county roads serving smaller communities. Approximately 21 miles (34 km) between Independence and Manchester go over a terminal moraine and enter the Driftless Area, a region it will not exit until Stockton, Illinois. The Freeway ends at Delaware.

At Delaware, US 20 becomes 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 (passing near the Field of Dreams filming site), Farley, Epworth, and Peosta before entering Dubuque. US 20 remains at least four lanes through Dubuque, but there are several stoplights along the route, particularly on the western edge of the city. There is a brief controlled-access section where the highway descends into the Mississippi River valley. Near the river, Locust Street connects US 20 with U.S. Route 52, U.S. Route 61, and U.S. Route 151, which have entered the city from the south as an expressway and continue northward as a freeway. US 20 crosses from Iowa into Illinois via the Julien Dubuque Bridge.

U.S. Route 20 was designated in Iowa on October 16, 1926. The designation created a single route number for drivers to follow across the state from Sioux City to Dubuque; previously, three route numbers were used.

It is possible to drive most of US 20's former two-lane alignment from Moorland to Dubuque. Most of this routing (with the exception of Iowa Highway 57 from US 65 to Cedar Falls) is now under city and county control, but most of the guide signs remain from when US 20 followed this route. From Moorland, the highway's former alignment is U.S. Route 20 Business through Fort Dodge. At Webster County Route P59, it continues on Webster County Route D20. The road changes designations several times between this point and Iowa Falls, but its route is very clear. It follows US 65 north out of Iowa Falls to the junction of Iowa 57, then follows 57 to Cedar Falls. At Cedar Falls, the former alignment continues on US 218 to Broadway Street; through Waterloo, it follows Broadway to Franklin Street to Dubuque Road. Beyond Waterloo, the designation of the road again changes several times, but the route to follow remains clear. Between Dyersville and Farley, US 20 follows its historic alignment. At Farley, the former alignment follows Old Highway Road into Dubuque.

The first segment of US 20 in Iowa to become four lanes was a short expressway segment east of Moville, which opened in 1958. Another short expressway segment in the Dubuque area opened in 1959. The rest of the expressway from Sioux City to Moville opened in 1964. By 1979 the Sioux City bypass was complete, as well as the section from Iowa 17 to Interstate 35, and the section from Independence to Delaware. By the end of the 1980s, the four-lane portions of US 20 ran from Coalville (near Fort Dodge) to Interstate 35 and from Waterloo to Dubuque.

During the 1990s little work was done to the route. It was extended westward to US 169 in 1991, and eastward to US 65 the same year, though initially the section from I-35 to US 65 was only two lanes. The new, semi-controlled section in Dubuque opened in 1996. Work began to accelerate in 2000, with the section between Interstate 35 and U.S. Route 65 becoming four lanes that year. The segment from Iowa 14 to Cedar Falls also opened in 2000. By 2003, the highway was complete from Fort Dodge to Dubuque.

As of 2006, the state of Iowa was acquiring right of way to extend the US 20 expressway westward from Moorland to a point 1.5 miles (2.4 km) west of the current north junction with US 71. Paving work between Iowa Highway 4 and Moorland was completed in 2010 and the stretch was opened in December 2010. Between Iowa 4 and U.S. 71 culverts and bridges were being constructed in Sac County as of March 2011. IADOT expects completion of 4-lane to Sac County Road N14 by the end of 2012 and to U.S. 71 by the end of 2013.

West of US 71, the remaining length of US 20 (approximately 60 miles) faces an uncertain future. The state has stated its intention to finish the project, but has not formally committed to a completion date. Community leaders in the northwestern Iowa communities which would be served by a four-lane U.S. 20 continue to advocate for its completion, and impact studies are under way.