Globally, precipitation is expected to increase along with the rise of temperatures due to climate change, increasing the likelihood of freshwater intrusion into coastal ecosystems. In the spring and summer of 2019, heavy rainfall and snowmelt in the midwestern United States caused historic flooding of the Mississippi River, warranting two openings of the Bonnet Carré Spillway (BCS) to reduce pressure on levees in New Orleans, LA. These openings released an unprecedented volume of freshwater into Lake Pontchartrain and subsequently into the Mississippi Sound. This study investigated the impacts of these freshwater releases on populations of the eastern oyster Crassostrea virginica and water quality in the western Mississippi Sound and the Bay of St. Louis. Platforms housing oysters and water quality sensors that measured dissolved oxygen, salinity, and temperature were deployed at oyster reef sites. At each reef, native oyster populations were assessed via dredge sampling to determine oyster survival. After 13 days, deployed oysters suffered 100% mortality at all sites except the Henderson Point Reef and Kittiwake Reef, the sites farthest east of the BCS. On September 27, 2019, 62 days following the BCS closing, dredge sampling revealed no live native adult oysters or spat, even at sites where living oysters were collected earlier in the summer. If BCS openings increase in frequency or duration because of elevated precipitation, oyster populations in Mississippi could remain unsustainable for harvesting unless future freshwater intrusions are incorporated into management planning.