Floods in the Mississippi basin can have large negative societal, natural, and economic impacts. Understanding the drivers of floods, now and in the future, is relevant for risk management and infrastructure-planning purposes. We investigate the drivers of 100-yr-return lower Mississippi River floods using a global coupled climate model with an integrated surface water module. The model provides 3400 years of physically consistent data from a static climate, in contrast to available observational data (relatively short records, incomplete land surface data, transient climate). In the months preceding the model’s 100-yr floods, as indicated by extreme monthly discharge, above-average rain and snowfall lead to moist subsurface conditions and the buildup of snowpack, making the river system prone to these major flooding events. The meltwater from snowpack in the northern Missouri and upper Mississippi catchments primes the river system, sensitizing it to subsequent above-average precipitation in the Ohio and Tennessee catchments. An ensemble of transient forcing experiments is used to investigate the impacts of past and projected anthropogenic climate change on extreme floods. There is no statistically significant projected trend in the occurrence of 100-yr floods in the model ensemble, despite significant increases in extreme precipitation, significant decreases in extreme snowmelt, and significant decreases in less extreme floods. The results emphasize the importance of considering the fully coupled land–atmosphere system for extreme floods. This initial analysis provides avenues for further investigation, including comparison to characteristics of less extreme floods, the sensitivity to model configuration, the role of human water management, and implications for future flood-risk management.