1541 Hernando de Soto reaches the Mississippi River and names it ''Río de Espíritu Santo''.
1673 Louis Joliet and Jacques Marquette begin exploring the Mississippi River.
1673 French explorers Jacques Marquette and Louis Jolliet reach the Mississippi River and become the first Europeans to make a detailed account of its course.
1679 Europeans first visit Minnesota and see headwaters of Mississippi in an expedition led by Daniel Greysolon de Du Luth.
1682 Robert Cavelier de La Salle discovers the mouth of the Mississippi River, claims it for France and names it Louisiana.
1687 Explorer Robert Cavelier de La Salle, searching for the mouth of the Mississippi River, is murdered by his own men.
1811 The first steamboat to sail the Mississippi River arrives in New Orléans, Louisiana.
1835 The Treaty of New Echota is signed, ceding all the lands of the Cherokee east of the Mississippi River to the United States.
1855 The first bridge over the Mississippi River opens in what is now Minneapolis, Minnesota, a crossing made today by the Father Louis Hennepin Bridge.
1862 American Civil War: A flotilla commanded by Union Admiral David Farragut passes two Confederate forts on the Mississippi River on its way to capture New Orleans, Louisiana.
1862 American Civil War: Confederate troops evacuate Fort Pillow on the Mississippi River, leaving the way clear for Union troops to take Memphis, Tennessee.
1862 American Civil War: the Confederate ironclad {{Ship|CSS|Arkansas}} is scuttled on the Mississippi River after suffering damage in a battle with {{USS|Essex|1856|6}} near Baton Rouge, Louisiana.
1865 The steamboat ''Sultana'', carrying 2,400 passengers, explodes and sinks in the Mississippi River, killing 1,700, most of whom are Union survivors of the Andersonville and Cahaba Prisons.
1947 KTLA, the first commercial television station west of the Mississippi River, begins operation in Hollywood, California.
1976 The ferry ''George Prince'' is struck by a ship while crossing the Mississippi River between Destrehan and Luling, Louisiana. Seventy-eight passengers and crew die and only 18 people aboard the ferry survive.
1993 The Great Flood of 1993 ends at St. Louis, Missouri, 103 days after it began, as the Mississippi River falls below flood stage.
2007 The I-35W Mississippi River Bridge spanning the Mississippi River in Minneapolis, Minnesota, collapses during the evening rush hour.