Cairo is the southernmost city in Illinois and the county seat of Alexander County. A river city, Cairo has the lowest elevation of any location in Illinois and is the only Illinois city to be surrounded by levees. It is in the river-crossed area of Southern Illinois known as "Little Egypt", for which the city is named, after Egypt's capital on the Nile. The city is coterminous with Cairo Precinct.

The Mississippi River is the primary river, and second-longest river, of the largest drainage basin in the United States. From its traditional source of Lake Itasca in northern Minnesota, it flows generally south for 2,340 miles (3,766 km) to the Mississippi River Delta in the Gulf of Mexico. With its many tributaries, the Mississippi's watershed drains all or parts of 32 U.S. states and two Canadian provinces between the Rocky and Appalachian mountains. The main stem is entirely within the United States; the total drainage basin is 1,151,000 sq mi (2,980,000 km2), of which only about one percent is in Canada. The Mississippi ranks as the thirteenth-largest river by discharge in the world. The river either borders or passes through the states of Minnesota, Wisconsin, Iowa, Illinois, Missouri, Kentucky, Tennessee, Arkansas, Mississippi, and Louisiana.