It rises in Mower County, Minnesota and enters Iowa in northern Mitchell County. It flows generally southeast across rural Chickasaw, Bremer, and Buchanan counties, past Independence and Anamosa. Along its lower 25 mi (40 km) it turns east, forming the boundary between Clinton and Scott counties. It joins the Mississippi from the west approximately 10 mi (16 km) southwest of Clinton.
It defines the western boundary of the Driftless Area. While the Wapsi has a soft, recent catchment, the Driftless, to the east and north, tumbles down to the Mississippi in rugged canyons.
The name of the river in the Ojibwe language is Waabizipinikaan-ziibi ("river abundant in swan-potatoes"), on account of the large quantity of arrowheads or wild artichokes, known as "swan-potatoes" (waabizipiniin, singular waabizipin), once found near its banks. Severe flooding on the river in 1993, as part of the larger floods in region, caused widespread damage to the surrounding cropland.
The Wapsipinicon is known for excellent fishing for catfish, although it also contains northern pike, carp, sunfish, and walleye (in some areas).