AClimate change represents an increasing stressor on estuarine and coastal ecosystems. A series of simulations were run using the Integrated Compartment Water Quality Model to determine the magnitude of various mechanisms controlling the effect of climate warming on dissolved oxygen (DO) in the Chesapeake Bay. The results suggested that the average hypoxic volume in the summer would increase by 9% (410 Mm³) from 1995 to 2025 as air temperature increases by 1.06°C and water temperature by 0.9°C. The change in DO solubility contributes 55% of the total climate warming effect, biological rates 33%, and stratification 11%. The Rappahannock Shoal, a hydraulic control point, plays a major role in determining the effect of climate warming on DO in the Bay. Due to the abrupt change in bathymetry, the convergence between seaward-moving freshwater and landward-moving saltwater causes downwelling and enhanced vertical mixing which introduces surface water of higher temperature to the deep channel and accelerates organic matter remineralization and oxygen consumption in deep waters. Surface water DO concentrations will decrease under climate warming conditions due to lower DO solubility, reducing DO flux to the deep channel and contributing to hypoxia development. These findings provide critical information for future management decision making regarding the effects of climate warming on DO in Chesapeake Bay and other estuaries.