The route began at the Mississippi River with US 61 southwest of Keokuk ran north through Mount Pleasant and Iowa City to Cedar Rapids.

US 161 began on the US 61 bridge over the Des Moines River, which represents the border between Missouri and Iowa.

[5] As the highway headed due north towards Mount Pleasant, it passed many small communities, but did not enter any of them.

The road headed due north, jogging to the east only slightly to cross the Skunk River.

It entered the Cedar Rapids area from the southwest side, where it intersected US 30 and Iowa 64.

40, which was known as the Red Ball Route, from Keokuk to Cedar Rapids, and Primary Road No.

[6] The northernmost forty miles (64 km) of US 161 were a part of a territorial and military road from Dubuque to Iowa City.

A short section in Keokuk and the remainder of the route north of Cedar Rapids was graveled, but not paved.

[8] A $100 million bond bill ($1.77 billion in 2023 dollars[9]) passed and approved by a plebiscite in 1928 allowed paving to commence in earnest.

By 1930, a hard-surfaced road existed from the Missouri state line to Olds in Henry County (55 mi or 89 km) and from Iowa City to northeast of Cascade in Dubuque County (75 mi or 121 km).

From Keokuk to Cedar Rapids, it was replaced by US 218, which had previously ended at US 30 south of Vinton.

[3] From Cedar Rapids to Key West, it was replaced by US 151, which had previously only existed in Wisconsin.

US 151 was routed westward from Madison along US 18 to Dodgeville, then along US 118 to Dickeyville, then along US 61 into Iowa to Key West, and then along US 161 to Cedar Rapids.