New Madrid fault?
At its heyday, Cahokia was much closer to the meandering river. A bad flood could have been a problem but I think it would be like today...... a known problem
The old river courses are well mapped and certainly not where the river is today. A study of the maps would indicate if the old river bed was within the city.
A big flood would certainly cause the population to scatter. Plus there’s the possibility of causing famine due to the loss of crops and cropland.
Detroit is about 300 years old and it's lost over 60% of its peak 1950s population as sane people continue to flee from it. Destroying a city doesn't always require a natural disaster. Humans can do a great job of it on their own.
I wonder if an earthquake on the New Madrid fault triggered a disturbance in the Mississippi River causing a flood.
Some interesting info on the 1993 flood. http://www.nwrfc.noaa.gov/floods/papers/oh_2/great.htm