Increases in the frequency, duration, and severity of regional drought pose major threats to the health and integrity of downstream ecosystems. During 2007–2008, the U.S. southeast experienced one of the most severe droughts on record. Drought and water withdrawals in the upstream watershed led to decreased freshwater input to Apalachicola Bay, Florida, an estuary that is home to a diversity of commercially and ecologically important organisms. This study applied a combination of laboratory experiments and field observations to investigate the effects of reduced freshwater input on Apalachicola oysters. Oysters suffered significant disease-related mortality under high-salinity, drought conditions, particularly during the warm summer months. Mortality was size-specific, with large oysters of commercially harvestable size being more susceptible than small oysters. A potential salinity threshold was revealed between 17 and 25 ppt, where small oysters began to suffer mortality, and large oysters exhibited an increase in mortality. These findings have important implications for watershed management, because upstream freshwater releases could be carefully timed and allocated during stressful periods of the summer to reduce disease-related oyster mortality. Integrated, forward-looking water management is needed, particularly under future scenarios of climate change and human population growth, to sustain the valuable ecosystem services on which humans depend.