Eutrophication-induced coastal hypoxia can result in stressful habitat for marine living resources and cause great economic losses. Nutrient management strategies have been implemented in many coastal systems to improve water quality. However, the outcomes to mitigate hypoxia have been mixed and usually small when only modest nutrient load reduction was achieved. Meanwhile, there has been increasing recognition of climate change impacts on estuarine hypoxia, given estuaries are especially vulnerable to climate change with multiple influences from river, ocean and the atmosphere. Due to the limitation of observational studies and the lack of continuous historical data, long-term oxygen dynamics in response to the changes of external forces are still not well understood. This study utilized a numerical model to quantitatively investigate a century of change of Chesapeake Bay hypoxia in response to varying external forces in nutrient inputs and climate. With intensifying eutrophication since 1950, model results suggest an abrupt increase in volume and duration of hypoxia from 1950s-1960s to 1970s-1980s. This turning point of hypoxia might be related with Tropical Storm Agnes and consecutive wet years with relatively small summer wind speed. During 1985-2016 when the riverine nutrient inputs were modestly decreased, the simulated bottom dissolved oxygen exhibited a statistically significant declining trend of ~0.01 mgL-1yr-1 which mostly occurred in winter and spring. Warming was found to be the dominant driver of the long-term oxygen decline whereas sea level rise had a minor effect. Warming has overcome the benefit of nutrient reduction in Chesapeake Bay to diminish hypoxia over the past three decades. By the mid-21st century, the hypoxic and anoxic volumes are projected to increase by 10-30% in Chesapeake Bay if the riverine nutrient inputs are maintained at high level as in 1990s. Sea level rise and larger winter-spring runoff will generate stronger stratification and large reductions in the vertical oxygen supply to the bottom water. The future warming will lead to earlier initiation of hypoxia, accompanied by weaker summer respiration and more rapid termination of hypoxia. The findings of this study can help guide climate adaptation strategies and nutrient load abatement in Chesapeake Bay and other hypoxic estuaries.