A large body of scientific research has demonstrated a changing climate, which affects river flow regimes and extreme flood frequencies and magnitudes. The magnitude and frequency of extreme events are of critical importance in the evaluation of river systems to inform flood risk reduction under current and future conditions. The global climate projections from the Coupled Model Intercomparison Project, Phase 5 (CMIP5) datasets were used by the Variable Infiltration Capacity (VIC) land surface model to produce a runoff dataset, implementing a Bias-Correction Spatial Disaggregation (BCSD) approach. The resulting runoff was then used as input to the Routing Application for Parallel computatIon of Discharge (RAPID) river routing model to simulate daily flows within all 1.2 million Mississippi River Basin river reaches for years 1950 through 2099. This research effort analyzed the performance of the models for the historical time period, comparing with the observations at 64 gage locations for 16 different climate models. A recurrence interval analysis was performed to determine the 2-, 5-, 10-, 50-, 100-, 500-, and 1000-year events within both the historical and projected time periods, highlighting the relative changes predicted into the future. Anticipated seasonal changes are demonstrated by comparing monthly average streamflows for three different time periods (1951–2005, 2006–2049, and 2050–2099). Results indicate that the hydrologic conditions of the Lower Mississippi River are not stationary. Based on all 16 models considered in this study, the median of the model projections shows an 8% increase in the 100-year return period discharge at Vicksburg, Mississippi, into the future time period, although the full range of 16 models varies widely from − 11 to + 85% change in the 100-year discharge in the future.