I imagine it was as wild as the interior of South America's Amazon and Orinoco River valleys are today. I am curious what efforts, and by who, it took to transform that wilderness to what we have today? What species were lost in that transformation?
First off, it's worth noting that the Mississippi River system was heavily populated. Hundreds of cities across a few thousand years dominated the river system, using it as a highway system. We call these people the Mississippians and they were a collection of chiefdoms and city-states. So, people have always lived there.
Secondly, the same goes for the Amazon. It was heavily populated by the time Europeans wandered through. Local people did not live in a wilderness. Instead, they tamed the forest around them, creating a space for humanity to exist.
Both regions were depopulated greatly by European diseases (debatable, but up to 90% of the Americas may have died during the contact period), which often raced ahead of incoming Europeans.
Both places went "feral" after the collapse of all those societies. So, the state of wilderness experienced by incoming Europeans was an illusion.
Source: 1491: New Revelations About the Americas before Columbus by Charles C. Mann