The Mississippi River is the primary river of the largest drainage basin in the United States. It is the second-longest river in the United States, behind only the Missouri. From its traditional source of Lake Itasca in northern Minnesota, it flows generally south for 2,340 mi (3,770 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 river either borders or passes through the states of Minnesota, Wisconsin, Iowa, Illinois, Missouri, Kentucky, Tennessee, Arkansas, Mississippi, and Louisiana. 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 world's tenth-largest river by discharge flow, and the largest in North America.

Native Americans have lived along the Mississippi River and its tributaries for thousands of years. Many were hunter-gatherers, but some, such as the Mound Builders, formed prolific agricultural and urban civilizations, and some practiced aquaculture. The arrival of Europeans in the 16th century changed the native way of life as first explorers, then settlers, ventured into the basin in increasing numbers. The river served sometimes as a barrier, forming borders for New Spain, New France, and the early United States, and throughout as a vital transportation artery and communications link. In the 19th century, during the height of the ideology of manifest destiny, the Mississippi and several tributaries, most notably its largest, the Ohio and Missouri, formed pathways for the western expansion of the United States. The river also became the subject of American literature, particularly in the writings of Mark Twain.

Formed from thick layers of the river's silt deposits, the Mississippi embayment, and American Bottom are some of the most fertile regions of the United States; steamboats were widely used in the 19th and early 20th centuries to ship agricultural and industrial goods. During the American Civil War, the Mississippi's final capture by Union forces marked a turning point to victory for the Union. Because of the substantial growth of cities and the larger ships and barges that replaced steamboats, the first decades of the 20th century saw the construction of massive engineering works such as levees, locks and dams, often built in combination. A major focus of this work has been to prevent the lower Mississippi from shifting into the channel of the Atchafalaya River and bypassing New Orleans.

Since the 20th century, the Mississippi River has also experienced major pollution and environmental problems, most notably elevated nutrient and chemical levels from agricultural runoff, the primary contributor to the Gulf of Mexico dead zone.

The word Mississippi itself comes from Misi zipi, the French rendering of the Anishinaabe (Ojibwe or Algonquin) name for the river, Misi-ziibi (Great River).

In the 18th century, the river was set by the Treaty of Paris as, for the most part, the western border of the new United States. With the Louisiana Purchase and the country's westward expansion, it became a convenient boundary line between the western and eastern halves of the country. This is reflected in the Gateway Arch in St. Louis, which was designed to symbolize the opening of the West, and the focus on the "Trans-Mississippi" region in the Trans-Mississippi Exposition.

Regional landmarks are often classified in relation to the river, such as "the highest peak east of the Mississippi" or "the oldest city west of the Mississippi". The FCC also uses it as the dividing line for broadcast call-signs, which begin with W to the east and K to the west, overlapping in media markets along the river.

Due to its size and importance, it has been nicknamed The Mighty Mississippi River or simply The Mighty Mississippi.