The eastern oyster (Crassostrea virginica) is a robust fishery and aquaculture interest in the United States, especially along the gulf coast. Disease, habitat loss, overharvesting, and climate change have decimated oyster reefs across the U.S., with major losses in the southeast. Recent increases in freshwater inflow to the Mississippi Sound and Bight from frequent Bonnet Carré Spillway (BCS) – a flood control structure that diverts excess Mississippi River water away from New Orleans and into the western Mississippi Sound – openings have created even more vulnerable oyster populations. Therefore, we sought to understand how freshwater inflow from BCS operations has affected natural oyster mortality within the western Mississippi across time, and how these mortality trends compare to those across the coasts of North America. We used survey data to track changes in oyster mortality from 2011 – 2022 along with data on BCS operations to evaluate its contribution to the mortality trends. We additionally sourced field oyster mortality data from research across the eastern U.S. and the Gulf of Mexico for geographic comparison. Oyster mortalities were affected by interactions between freshwater discharge volume and distance to the BCS, maximum weekly temperatures and dissolved oxygen levels, and monthly rainfall and days of suboptimal salinity in the month leading up to sampling. The oyster mortalities during BCS operations were also higher than nearly all natural mortality rates reported in the literature. This study serves as the first effort to evaluate how freshwater inflow affects oyster survivorship in the Mississippi Sound and how BCS operations contribute to these natural mortality trends. Understanding the complex interactions between anthropogenic and environmental drivers of oyster mortality can support long term monitoring efforts and management decisions for these especially important organisms and their reefs.