At the time of European contact, the Kalamazoo River area was inhabited primarily by members of Potawatomi tribes.

The Jesuit priest Father Jacques Marquette and his companions were probably the first Europeans to glimpse the mouth of the Kalamazoo in 1675 as they returned from Illinois.

By the mid-19th century, several communities had grown up along the River as mill towns and commercial centers: Battle Creek, Kalamazoo, Parchment, Plainwell, and Otsego.

Although today the river is cleaner, the persistent PCB contamination has led to Superfund designation of a 35-mile (56 km) section from Kalamazoo to Allegan Dam.

A municipal area sewer system branch has been added and great efforts are being made to educate lake users about keeping fuels, lawn chemicals and fertilizers, etc.

Although the word Kalamazoo appears to be Native American in origin, the exact meaning is obscure and various definitions have been suggested.

On 26 July 2010, an Enbridge Energy pipeline leaked more than 1 million US gallons (3,800 m3) of tar sands also known as dilbit into Talmadge Creek that flows into the Kalamazoo, initially causing two homes to be evacuated, and prohibitions against fishing and swimming to be posted.

[11] The National Transportation Safety Board stated the Enbridge oil spill is the costliest onshore cleanup in U.S.