The eastern oyster is an integral part of the heritage, economy, and ecology of the northern Gulf region. In Mississippi, oyster populations have suffered several mass-mortality events since the Deepwater Horizon disaster, driven largely by climate-related extreme precipitation events that alter water quality conditions. Oyster reef restoration and revitalization of the oyster industry are top priorities for the State of Mississippi, yet effective planning and implementation require a better understanding of the complex interactions among management actions and the factors influencing oyster abundance, health, and survival. The Mississippi Based RESTORE Act Center of Excellence (MBRACE)is a consortium of the state’s four major research universities with the mission to support the sustainable use of coastal resources through a comprehensive understanding of the dynamic Mississippi Sound ecosystem. Using a structured decision-making approach, we characterized the decision context surrounding oyster restoration to help identify research and management priorities needed for the recovery of a sustainable oyster resource. We applied the Driver–Pressure–State–Impact–Response (DPSIR) framework as a conceptual model to illustrate the existing knowledge and challenges to facilitating healthy and sustainable oyster production with economic, ecological, and social co-benefits for the citizens of Mississippi. Key challenges include the impacts of freshwater inputs from the Bonnet Carré Spillway opening and water quality impairments in shellfish-growing areas caused by increased runoff during heavy rainfall events. The DPSIR framework enables MBRACE researchers to more effectively communicate scientific findings to resource managers and policy makers, informing restoration and management decisions while highlighting knowledge gaps to guide future research efforts, climate-driven environmental variability remains a major source of uncertainty for oyster restoration and management, underscoring the need for applied research to support the decision making process.