The southern terminus of Iowa Highway 5 is at the Missouri border southwest of Cincinnati.

It passes through Cincinnati, then turns north to go through Centerville, where it intersects Iowa Highway 2.

Iowa 5 then continues west as a southeastern freeway bypass of Des Moines, intersecting Iowa Highway 28 at Norwalk and ends in West Des Moines at Interstate 35.Primary Road 5 was designated in 1920 connecting Sioux City and Dubuque.

In 1926, this route was truncated at Fort Dodge and at Le Mars and subsequently extended to Akron in 1929.

In the Des Moines area, Iowa 5 had the same route along Army Post Road from 1969 until 1997, when sections of a southern bypass, completed in 2002, were opened.