It drains a rural farming region of rolling hills and bluffs north of Waterloo and Cedar Rapids.

It flows generally southeast across rural Chickasaw, Bremer, and Buchanan counties, past Independence and Anamosa.

While the Wapsi has a soft, recent catchment, the Driftless, to the east and north, tumbles down to the Mississippi in rugged canyons.

[7] The Wapsipinicon River runs alongside the Iowa cities and communities of McIntire, Riceville, Deerfield, Elma, Frederika, Tripoli, Littleton, Otterville, Independence, Quasqueton, Troy Mills, Paris, Central City, Waubeek, Stone City, Anamosa, Olin, Oxford Junction, Oxford Mills, Massillon, Toronto, Wheatland, McCausland, Folletts, and Shaffton before emptying into the Mississippi River.

[8] The Wapsipinicon is known for excellent fishing for catfish, although it also contains abundant northern pike, carp, sunfish, and walleye (in some areas).