Symbolism, Imagery, Allegory
Considering that it's right there in the title, it's no stretch to say that the Mississippi River is the most important symbol in the book. Throughout, the Mississippi giveth and the Mississippi taketh away. It divides people and brings them together, and finally, it becomes a metaphor for time itself, which also divides people and brings them together.
Let's look first at the river as a physical object. This isn't the first book to make use of the Mississippi River, and no wonder. Running from the Great Lakes to the Gulf of Mexico, the river divides the United States and continues to be a major source of transportation to this day. You know what else divides the United States? The Civil War.
Before the book even begins, the river has taken Paw away. He's working the river somewhere, a fate Mama fears will take Noah, too:
Long before people began hollering war, Mama was already afraid she'd lose Noah. Most boys hankered to go on the river. […] What a worry this had always been to Mama. (3.7)
Like the war, the river and its allure are this sort of overwhelming force. Adding to this is the fact that the river is also a major source of anxiety for Cass, whose visions seem to center around bad things that happened on the river centuries ago. The river is vast and ominous and ever-present. But, the river also gives back. After all, it's what brings Delphine and Calinda to Grand Tower.
The battle Noah fights in is for control of the river, a key and contested point during the Civil War because of its value for transportation and control of the states that border it:
It was famous, the Battle of Belmont, Missouri. It sparked the career of General U.S. Grant and led him in time to the White House as President. It was the first struggle for the Mississippi, that great highway flowing between my Grand Tower and Delphine's New Orleans. (13.16)
For Dr. Hutchings, the river comes to have a different meaning, as he operates on a steamboat-turned-hospital ship after the battle. "We were on the boat when I took it," he says of Noah's arm. "I put it overboard. I gave it to the river. […] I gave them all to the river" (13.30-31). Here the river becomes almost god-like, something to be given gifts of human sacrifice. And again, we see its power reinforced.
Later in Tilly's life, the river divides the old people in the House Astride the Devil's Backbone from their son and his family in St. Louis. As Howard notes, Tilly compares time to the river. "She said time was like the Mississippi River. It only flows in one direction. She meant you could never go back. But of course we had. She'd taken me back" (15.37). Looks like the river might not have been quite so big as it's seemed this whole time … just like individual events in life, and even war, diminish in retrospect.