The impacts of dams and levees on the long-term (>130 years) discharge record was assessed along a ~1200 km segment of the Mississippi River between St. Louis, Missouri, and Vicksburg, Mississippi. To aid in our evaluation of dam impacts, we used data from the U.S. National Inventory of Dams to calculate the rate of reservoir expansion at five long-term hydrologic monitoring stations along the study segment. We divided the hydrologic record at each station into three periods: (1) a pre-rapid reservoir expansion period; (2) a rapid reservoir expansion period; and (3) a post-rapid reservoir expansion period. We then used three approaches to assess changes in the hydrologic record at each station. Indicators of hydrologic alteration (IHA) and flow duration hydrographs were used to quantify changes in flow conditions between the pre- and post-rapid reservoir expansion periods. Auto-regressive interrupted time series analysis (ARITS) was used to assess trends in maximum annual discharge, mean annual discharge, minimum annual discharge, and standard deviation of daily discharges within a given water year. A one-dimensional HEC-RAS hydraulic model was used to assess the impact of levees on flood flows. Our results revealed that minimum annual discharges and low-flow IHA parameters showed the most significant changes. Additionally, increasing trends in minimum annual discharge during the rapid reservoir expansion period were found at three out of the five hydrologic monitoring stations. These IHA and ARITS results support previous findings consistent with the observation that reservoirs generally have the greatest impacts on low-flow conditions. River segment scale hydraulic modeling revealed levees can modestly increase peak flood discharges, while basin-scale hydrologic modeling assessments by the U.S. Army Corps of Engineers showed that tributary reservoirs reduced peak discharges by a similar magnitude (2 to 30%). This finding suggests that the effects of dams and levees on peak flood discharges are in part offsetting one another along the modeled river segments and likely other substantially leveed segments of the Mississippi River.