It continues east from South English through Kinross and Wellman before intersecting Iowa Highway 1 at Kalona.

It then turns east along a route next to the Mississippi River and passes through Buffalo before intersecting Interstate 280 at Davenport.

The segment of the highway between Muscatine and Davenport is part of the Great River Road.

For years, several sections of Iowa Highway 22 was either gravel or had a bituminous surface.

One of these sections — the section between Muscatine and Blue Grass — was paved in 1957, the same year U.S. 61 and Iowa Highway 22 switched routes; U.S. 61 now went through Blue Grass, while Iowa Highway 22 now followed the Mississippi River through Buffalo.