Abstract Climate change is known to cause deoxygenation in the open ocean, but its effects on eutrophic and seasonally hypoxic estuaries and coastal oceans are less clear. Using Chesapeake Bay as a study site, we conducted climate downscaling projections for dissolved oxygen and found that the hypoxic and anoxic volumes would increase by 10–30% between the late 20th and mid-21st century. A budget analysis of dissolved oxygen in the bottom water revealed differing physical and biogeochemical responses to climate change. Sea level rise and larger winter-spring runoff led to stronger stratification and large reductions in the vertical oxygen supply to the bottom water. On the other hand, warming led to earlier initiation of hypoxia, accompanied by weaker summer respiration and more rapid termination of hypoxia. Decreasing solubility due to warming accounted for about 50% of the reduction in the bottom-water oxygen content.