Indeed. Also the Ohio River was another trade superhighway, with short portages to Lake Erie and the rivers that fed into the Atlantic.
I’m convinced that Europeans arrived here during the American “Dark Ages”—the occupation of barbarian tribes after the fall of a great civilization or complex of civilizations. Cahokia was its Rome, and its lingering vestiges were seen by De Soto and others in the historical Mississippian populations in the Southeast.
The Lenape had legends of a great civilization to the West, the Alligewi, who they and the Iroquois teamed up to destroy.
These things produce large quantities of caffein.
Worth noting ~ many analysts through the centuries, starting with the first Spanish explorers on the scene, have judged Cahokia to have some contact with CHINA.
This is about as far North as you can go in a serious ship (before modern dredging techniques and the development of a system of locks and dams along the upper Mississippi and the Missouri rivers.
About 800 AD somebody ~ no one knows who ~ showed up with the Old World invention called THE BOW AND ARROW. There are no traces before that period. Many have speculated that some folks with a taste for tea showed up at the same time.
Cahokia was developed on a long occupied area, but this town grew to have about 50,000 people making it the largest city North of Mexico City. The first traces of the dominant culture (with their totemic animals, ceremonial songs, dances and so forth) showed up about 700 AD ~ there was a big spike in cultural advance for the next couple of centuries, and by 1500, although it was still in business, they got wiped out by the great hanta virus epidemic that'd swept both North and South America (coincident with but not caused by European discovery ~ this stuff killed the Europeans as well).
It was so difficult to build up populations, whether native, or African, or European, during that period (hanta virus plague) that Europeans focused their efforts on mostly the offshore islands.
Finally, some time in the late 1500s things opened up a bit in South and Central America, and even in North America.
By the mid 1600s the plague had returned to North America but Europeans were too engaged in the 30 years war to much care. Major development didn't begin again until the late 1600s ~ first Bacon's Rebellion, the Pequot War, and a couple of other things demonstrated dissatisfaction with the Old Order of private development companies, and both led directly to the imposition of Crown Colonies on all the English claimed areas (and some of the French and Spanish claims as well).
In the meantime ~ mid 1500 to late 1600s there were some brave souls who were undoubtedly naturally immune to cholera, undulent fever, influenza, black plague, typhod, typhus and maybe a dozen other common ailments found in the then American heartland
They left some markers of their own behind as they did surveys and inventories of resources.