It begins at the Missouri state line southwest of Bloomfield and travels north through Ottumwa, Oskaloosa, Tama, Waterloo, and New Hampton.

While US 63 was created in 1926, it dates back eleven years prior to the creation of the Daniel Boone Trail, which sought to be the best north–south highway in an era when most routes traveled from east to west.

Upon creation of the primary highway system in 1920, the Daniel Boone Trail was assigned a series of route numbers.

Instead of turning to the northwest at Oskaloosa, it now traveled north through Tama, Waterloo, and New Hampton, eventually reaching Lake Superior at Ashland, Wisconsin.

In the 1990s and 2000s, large parts of the US 63 corridor found itself removed from planning budgets while other portions of the route were widened to four lanes.

The two highways cross the Des Moines River and curve around the downtown area of Ottumwa until they reach Iowa 163.

The freeway bypasses Ottumwa to the east and then curves around to the north; a couple interchanges serve local traffic.

Prior to the mid-1990s, it met Iowa 85 at an intersection with Main Street; that highway was turned back to the eastern city limits in 1994.

Continuing north, the highway passes Buckingham to the west and then intersects Iowa 175 not long after crossing into Black Hawk County.

The four-lane road curves along the north side of town and meets the northern end of the business route.

It travels through rural Chickasaw and Howard counties until it reaches Iowa 9 roughly midway between Riceville and Cresco.

Then, the road was maintained by the Daniel Boone Trail Association, which solicited donations from people who lived along the route.

The route was intended to travel from St. Louis, Missouri, to St. Paul, Minnesota, by way of Ottumwa, Oskaloosa, Des Moines, Boone, Fort Dodge, Humboldt, and Algona.

"[19] In 1919, the Iowa General Assembly passed a bill that created a fund for improving and hard-surfacing nearly 6,300 miles (10,100 km) of primary roads in the state.

The national northern end of the highway was at the corner of Grand Avenue and E. 14th Street near the Iowa State Capitol where US 32 and US 65 split.

[23] When it was designated, only a small percentage of the route was paved – a short section south of Oskaloosa and all it in Polk County.

Due to the major change in the route, the abandoned segment from Oskaloosa to Des Moines was renumbered U.S. Highway 163.

The rest of the western Waterloo highway was delayed by the city so the Army Corps of Engineers could complete a study on flood control in the downtown area.

[50] A 4-cent-per-US-gallon (1.1 ¢/L) increase in Iowa's gas tax in 1988 (equivalent to 10 ¢/US gal [2.6 ¢/L] in 2023 dollars[51]) also added some much needed funds for highway construction.

[57] In 1996, the Iowa Transportation Commission approved an ambitious, $1.7-billion highway construction plan (equivalent to $3.05 billion in 2023 dollars[36]) that would expand six important corridors to four-lane expressways—and not freeways—including the Des Moines to Burlington route, by 2004.

[65] Budget constraints in the early part of the 2000s caused the Iowa DOT to table some highway projects, but they were still committed to completing the six high-priority corridors.

[67][72] The new road shifted US 63 traffic out of downtown and onto US 34 heading east from the intersection of the two highways near the city's John Deere plant.

Governor Chet Culver presided over the ribbon cutting ceremony that celebrated the opening of the Fairfield bypass and the completion of the 1996 highway plan.

[73] Plans for a bypass in New Hampton started in the early 1990s after a study reported that building a four-lane road that connected Waterloo and Rochester, Minnesota, was economically feasible.

Fourteen people died in accidents on the 15 miles (24 km) between the two cities from 1986 to 1994, so the announcement was welcomed by local residents.

The transition from four lanes to two presented a few dangers – four-lane traffic must slow down from 65–70 to 55 mph (105–115 to 90 km/h) and then the two-lane road itself was in rough shape.

Most frustrating to some was that the DOT already owned the right-of-way for the expanded highway, but they chose to allow farmers to grow oats on the land instead.

[80] Near Frederika, where the new highway bypassed two 90-degree curves, dirt fill was used from a nearby property that was slated for wetland restoration near the Wapsipinicon River.

[83] A tax increment financing district was created along Logan Avenue and through eastern Waterloo with the hope that the rebuilt highway would be a catalyst to economic growth.

[86] The completed road reopened on November 1, 2019; civic and business leaders held a small ceremony at the foot of the viaduct to celebrate its opening.