Southern Illinois is a region of the U.S. state of Illinois comprising the southern third of the state, principally south of Interstate 70. Part of downstate Illinois, it is bordered by the two most voluminous rivers in the United States: the Mississippi below its connection with the Missouri River to the west and the Ohio River to the east and south, with the tributary Wabash River, extending the southeastern border. Some areas of Southern Illinois are known historically as Little Egypt. Although part of the Midwest, certain areas of Southern Illinois more closely align culturally with neighboring parts of the Upland South (i.e. Kentucky, Tennessee, Southern Indiana, and Missouri).

Southern Illinois' most populated city is Belleville at 44,478. Other principal cities include Alton, Centralia, Collinsville, Edwardsville, Glen Carbon, Godfrey, Granite City, O'Fallon, Harrisburg, Herrin, West Frankfort, Mt. Vernon, Marion, and Carbondale, where the main campus of Southern Illinois University is located. Residents may also commute to St. Louis and Cape Girardeau, Missouri; Evansville, Indiana; and Paducah, Kentucky. The region is home to Scott Air Force Base, a major military installation.

The area has a population of 1.2 million people, who live mostly in rural towns and cities separated by extensive farmland and the Shawnee National Forest. The two higher density areas of population are Metro East (pop. 700,000+), which is the partly industrialized Illinois portion of the St. Louis Metropolitan Area, and the Carbondale–Marion–Herrin, Illinois Combined Statistical Area, centered on Carbondale and Marion, a two-county area that is home to 123,272 residents.

The first European settlers were French colonists in the part of their North American territory called Illinois Country. Later settlers migrated from the Upland South of the United States, traveling by the Ohio River. The region was affiliated with the southern agricultural economy, based on enslaved African Americans as workers on major plantations, and rural culture. Some settlers owned slaves before the territory was organized and slavery was prohibited. Many areas developed an economy based on coal mining.

The earliest inhabitants of Illinois are thought to have arrived about 12,000 BC. They were indigenous hunter-gatherers, but they also developed their own system of agriculture. After AD 1000, the production of agricultural surpluses resulted in the development of complex, hierarchical societies. With the rise of the Mississippian culture in the Mississippi and Ohio River valleys, tribal leaders organized thousands of workers to build complex urban areas featuring numerous large earthworks – pyramidal, ridgetop and conical mounds used for religious, political and ceremonial purposes. Cahokia, located within the boundaries of present-day Collinsville, Illinois, was the major regional center of this culture. It contains the largest prehistoric earthworks in the Americas, and has been designated as a UNESCO World Heritage Site. The mound builders' culture seems to have collapsed between AD 1400–1500. The Mississippians had abandoned Cahokia long before the first European explorers arrived.

The Illinois tribes, for whom the state is named, and other historic tribes migrated to Southern Illinois around AD 1500. Archaeologists say they were not descendants of the earlier inhabitants; they spoke an Algonquian language of Miami-Illini, shared in dialects among neighboring regional tribes. They had likely migrated from eastern areas, where Algonquian-language tribes emerged along the Atlantic Coast and waterways. The Illini left numerous artifacts, including burial sites, burned-out campfires along the bases of bluffs, pottery, flint implements, and weapons. Structures built by them include stone forts or "pounds". Visitors can see a stone fort in Giant City State Park near Makanda. At least eight other such structures are known in the region.

In about 1673, French explorers from Quebec became the first Europeans to reach Illinois. The French named the area Illinois after the Indians who had greeted them. The French explored the Mississippi River, establishing outposts and seeking a route to the Pacific Ocean and the Far East. As increasing Indian unrest and warfare began in Northern Illinois over the lucrative fur trade along the Great Lakes, the French concentrated on building outposts in Southern Illinois. The earliest European settlers were concentrated along the Mississippi, Ohio, and Wabash rivers, which provided easy routes for travel and trade. The settlements including Cahokia town, Kaskaskia and Chartres became important market villages and supply depots between Canada and the French ports on the lower Mississippi River. Other important early outposts in Southern Illinois were at Old Shawneetown and Fort Massac on the Ohio River.

After defeating the French in the French and Indian War (Seven Years' War) and signing the Treaty of Paris in 1763, the English ruled the Great Lakes region. At the time, many French settlers moved from towns on the eastern side of the Mississippi to the western side, which was ruled by Spain after the war. It took over all the Louisiana Territory west of the river. During the American Revolutionary War, the Southern Illinois area was the scene of the best known campaign in what was then the American west, when Virginians sought to occupy it against the British.