The fishery for eastern oyster Crassostrea virginica in Chesapeake Bay, USA, was the biggest oyster fishery in the world and the largest fishery in the US in the late 1800s. The population has declined substantially because of overfishing, disease, and habitat loss. We developed a statistical model to simultaneously estimate effects of fishing and disease on oysters in upper Chesapeake Bay during 1980 to 2009. We compared the model estimates of abundance in 2009 to that prior to large-scale commercial fishing. We found that oyster abundance declined 99.7% (90% credibility interval [CI], 98.3 to 99.9%) since the early 1800s and 92% (90% CI, 84.6 to 94.7%) since 1980. Habitat area declined nearly 70% (90% CI, 36.2 to 83.3%) during 1980 to 2009. Natural mortality (mortality from all non-fishing sources) of market-sized oysters varied substantially and increased during 1986 to 1987 and 2000 to 2002, and natural mortality of small oysters approximately doubled after 1986. The exploitation rate varied over time and averaged 25.1% yr -1 (90% CI, 16.1 to 33.1%) during 1980 to 2008. Fishing and disease have had substantial negative impacts on the population, but effects of fishing have been stronger than increased natural mortality. We recommend a moratorium on fishing to minimize the risk of extirpation and provide an opportunity for recovery.