Iowa 16 begins at an interchange with US 34 three miles (4.8 km) east of Agency in Wapello County.

On the east side of Eldon, tourists are directed to the American Gothic House, made famous by the painting by Iowa artist Grant Wood.

Southeast of Eldon, the road clips the northeastern corner of Davis County as it runs through the river's floodplain to Selma.

The road goes through a series of curves that take it further south until it straightens out near the northern intersection with Iowa 1.

It runs due east through Houghton and then meets the four-lane US 218 / Iowa 27, the Avenue of the Saints highway, at an at-grade intersection.