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Abstract The Mississippi River is the largest commercial waterway in North America and one of the most heavily engineered rivers in the world. Future alteration of the river’s hydrology by climate change may increase the vulnerability of flood mitigation and navigation infrastructure implemented to constrain 20^thcentury discharge conditions. Here, we evaluate changes in Lower Mississippi River basin hydroclimate and discharge from 1920–2100 C.E. by integrating river gauge observations and climate model ensemble simulations from CESM1.2 under multiple greenhouse gas emissions scenarios. We show that the Lower Mississippi River’s flood regime is highly sensitive to emissions scenario; specifically, the return period of flood discharge exceeding existing flood mitigation infrastructure decreases from approximately 1000 years to 31 years by the year 2100 under RCP8.5 forcing, primarily driven by increasing precipitation and runoff within the basin. Without aggressive reductions in greenhouse gas emissions, flood mitigation infrastructure may require substantial retrofitting to avoid disruptions to industries and communities along the Lower Mississippi River.