At the time white explorers first began arriving, the area was home to the Potawatomi, and the settlers began to arrive in 1829. In 1829 Titus Bronson built the first cabin within the modern city limits.

Kalamazoo was originally a Native American name although its exact origin hasn't been isolated; it is thought that it means "the mirage of reflecting river," while others say it means bubbling or boiling water. Intrigued by the name, many poets, authors and songwriters have penned Kalamazoo into their creative works. The most notable of which may be Glenn Miller's I've Got a Gal in Kalamazoo. The earliest residents of the area were the "Moundbuilders," an early race of Native Americans that subsisted on farming.

Other notable historical tidbits include: in 1959 Kalamazoo designed the first pedestrian mall in the US; the Gibson Mandolin-Guitar Manufacturing Company was founded to market the instruments; and, the Michigan Central line first spanned the territory between Detroit and Kalamazoo in 1846. The link to Chicago was completed in 1852. By 1905 at least six railroads connected Kalamazoo with the rest of the country.