Cahokia, the center of the Native American Mississippian culture was located in southern Illinois near present-day Collinsville. When the Mississippian culture disappeared, a political alliance of several tribes, the Illinwek Confederation dominated the region, until they in turn were replaced by the Potawatomi, Miami and Sauk tribes.

Probably the first Europeans to visit the area were the French explorers Jacques Marquette and Louis Joliet, in 1673. As a result, Illinois was part of the French empire until 1763. However, following the Seven Years' War (generally known in the US as the "French and Indian War"), control of the area passed to Britain. In 1783, after the American Revolution, the area became part of the United States' Northwest Territory.

The Illinois Territory was created in 1809, and in 1818 Illinois was admitted to the United States as the 21st state, the last Native American tribes being driven out in 1832.

Illinois served an important part in the American Civil War (1861 to 1865), and contributed over 250,000 men to the Union Army, more than any other northern state except New York, Pennsylvania and Ohio. These men in total mustered 150 infantry regiments, 17 cavalry regiments, and 2 light artillery regiments.

The state was struck by disaster in 1871 when fire broke out in Chicago. This fire, known as the "Great Chicago Fire" killed hundreds and destroyed about 4 square miles (10 km²). Even today, this event is remembered: the second star of the city's municipal flag commemorates the event.

Illinois was continued to grow in the 20th century, and among other things is notable as the site of the first nuclear power generating reactor (Argonne National Laboratory near Chicago in 1957), and the first McDonald's franchise (Des Plaines in 1960).