During the American Civil War Natchez was surrendered by Confederate forces without a fight in September 1862. Following the Union victory at the Battle of Vicksburg in July 1863, many refugees, including former slaves, freed by the Emancipation Proclamation, began moving into Natchez and the surrounding countryside.

The Baton Rouge area owes its historical importance to its strategic site upon the Istrouma Bluff, the first natural bluff upriver from the Mississippi River Delta at the Gulf of Mexico. This allowed development of a business quarter safe from seasonal flooding.

East of Napoleon, The Beulah Bend (now Lake Beulah) was a 10-mile arc of the Mississippi River that started at the mouth of the Arkansas and semi-circled back around to within a mile of the Arkansas river's mouth.[6][7] During the American Civil War, 

Because of Vicksburg's location on the Mississippi River, it built extensive trade from the prodigious steamboat traffic in the 19th century. It shipped out cotton coming to it from surrounding counties and was a major trading city in West Central Mississippi.

Clemens visited the town frequently during his piloting days on the Mississippi River.  In June of 1858 he spent a week there while his brother, Henry, was in hospital after the Pennsylvania's explosion.

Mark Twain was again in Memphis in 1882.  From Life on the Mississippi:

Cairo, Illinois is a significant location in Mark Twain’s book “Adventures of Huckleberry Finn”. The confluence of the Ohio and Mississippi Rivers is where Jim hopes to escape to freedom, abandoning their raft and taking a steamboat up into the free state of Ohio. Huck and Jim never reach Cairo.