The area on which the modern city of Kalamazoo stands was once home to Native Americans of the Hopewell culture, who migrated into the area sometime before the first millennium. Evidence of their early residency remains in the form of a small mound in downtown's Bronson Park. The Hopewell civilization began to decline after the 8th century and was replaced by other groups. The Potawatomi culture lived in the area when the first European explorers arrived.

René-Robert Cavelier, Sieur de La Salle, passed just southeast of the present city of Kalamazoo in late March 1680. The first Europeans to reside in the area were itinerant fur traders in the late 18th and early 19th century. There are records of several traders wintering in the area, and by the 1820s at least one trading post had been established.

During the War of 1812, the British established a smithy and a prison camp in the area.

The 1821 Treaty of Chicago ceded the territory south of the Grand River to the United States federal government. However, the area around present-day Kalamazoo was reserved as the village of Potawatomi Chief Match-E-Be-Nash-She-Wish. Six years later, as a result of the 1827 Treaty of St. Joseph, the tract that became the city of Kalamazoo was also ceded.

In 1829, Titus Bronson, originally from Connecticut, became the first white settler to build a cabin within the present city limits of Kalamazoo. He platted the town in 1831 and named it the village of Bronson—not to be confused with the much smaller Bronson, Michigan, about fifty miles (80 km) to the south-southeast of Kalamazoo.

Bronson, frequently described as "eccentric" and argumentative, was later run out of town. The village was renamed Kalamazoo in 1836, due in part to Bronson's being fined for stealing a cherry tree. Today, a hospital and a downtown park, among other things, are named for Bronson. Kalamazoo was legally incorporated as a village in 1838 and as a city in 1883.

The fertile farmlands attracted prosperous Yankee farmers who settled the surrounding area, and sent their sons to Kalamazoo to become businessmen, professionals and entrepreneurs who started numerous factories. Most of the original settlers of Kalamazoo were New Englanders or were from upstate New York.

In the 1940s, the city became the first to install curb cuts.

In 1959, the city created the Kalamazoo Mall, the first outdoor pedestrian shopping mall in the United States, by closing part of Burdick Street to auto traffic. The Mall was designed by Victor Gruen, who also designed the country's first enclosed shopping mall, which had opened three years earlier. Two of the mall's four blocks were reopened to auto traffic in 1999 after much debate.

An F3 tornado struck downtown Kalamazoo on May 13, 1980, killing five and injuring 79.

On February 20, 2016, Kalamazoo became the site of a random series of shootings in which six people were killed. A prime suspect was apprehended by police without incident.

In the past, Kalamazoo was known for its production of windmills, mandolins, buggies, automobiles, cigars, stoves, paper, and paper products. Agriculturally, it once was noted for celery. Although much of it has become suburbanized, the surrounding area still produces farm crops, primarily corn and soybeans.

Kalamazoo was the original home of Gibson Guitar Corporation, which spawned the still-local Heritage Guitars. The company was incorporated as "Gibson Mandolin - Guitar Co., Ltd" on October 11, 1902, by the craftsman Orville Gibson. One budget model was named the Gibson Kalamazoo "Melody Maker" Electric Guitar. Operations were moved gradually from Kalamazoo to Memphis, Tennessee, (Electric Division) and Bozeman, Montana, (Acoustic Division) in the 1980s. Some workers from the original factory stayed in Kalamazoo to create the Heritage Guitar company.

Kalamazoo was once known as the "Paper City" because of the paper mills in and near the city. The Allied Paper Corporation operated several mills and employed 1,300 people in Kalamazoo during the late 1960s. As the forests of West Michigan were logged out, paper mills closed.

Early in the 20th century, Kalamazoo was home to the brass era automobile company Barley.

Kalamazoo was also headquarters of the Checker Motors Company, the former manufacturer of the Checker Cab, which also stamped sheet metal parts for other auto manufacturers. Checker closed on June 25, 2009, a victim of the Late-2000s recession.

As of 2000, the median income for a household in the city was $31,189, and the median income for a family was $42,438. Males had a median income of $32,160 versus $25,532 for females. The per capita income for the city was $16,897. About 13.6% of families and 24.3% of the population were below the poverty line, including 26.0% of those under age 18 and 11.3% of those age 65 or over.

As of the census of 2010, there were 74,262 people, 29,141 households, and 13,453 families residing in the city. The population density was 3,009.0 inhabitants per square mile (1,161.8/km²). There were 32,433 housing units at an average density of 1,314.1 per square mile (507.4/km²). The racial makeup of the city was 68.1% White, 22.2% African American, 0.5% Native American, 1.7% Asian, 2.8% from other races, and 4.6% from two or more races. Hispanic or Latino of any race were 6.4% of the population.

There were 29,141 households, of which 25.8% had children under the age of 18 living with them, 26.1% were married couples living together, 15.6% had a female householder with no husband present, 4.5% had a male householder with no wife present, and 53.8% were non-families. 36.8% of all households were made up of individuals, and 9.3% had someone living alone who was 65 years of age or older. The average household size was 2.29 and the average family size was 3.04.

The median age in the city was 26.2 years. 20.5% of residents were under the age of 18; 27% were between the ages of 18 and 24; 24.9% were from 25 to 44; 18.2% were from 45 to 64; and 9.4% were 65 years of age or older. The gender makeup of the city was 49.3% male and 50.7% female.