In this study, a terrestrial-estuarine-ocean biogeochemical modeling system (DLEM-ChesROMS-ECB) was used to investigate the impact of prevailing spring-to-summer winds on hypoxia in Chesapeake Bay. The modeling system was run continuously from 1985 to 2005 under realistic wind conditions. Correlation analysis based on the 21-year simulation results revealed that the durations of spring northeasterly winds and summer southerly winds were both positively correlated with the volume of summer hypoxia. Conversely, the duration of summer northeasterly winds was negatively correlated with hypoxia. We then conducted multiple idealized sensitivity experiments to explore the underlying mechanisms governing these relationships. The results indicated that prolonged northeasterly winds in spring promoted along-channel transport of oxygen-consuming materials from the upper to the lower Bay, leading to a higher level of oxygen consumption via water column respiration (WCR). This may have led to more severe hypoxic events in the following summer. During summer, northeasterly winds increase vertical mixing as the riverine freshwater is mostly restricted to the western bank, thereby preventing the occurrence of hypoxia. Furthermore, strengthened vertical mixing increased light availability, resulting more nutrients taken up by phytoplankton. Consequently, more dissolved oxygen was produced. When comparing the differences in mass budget terms under southerly winds, the oxygen production accounted for approximately 60% of the WCR. In contrast to previous studies that mostly examined the short-term episodic effects of wind, our study underscores the importance of the impact of prolonged seasonally variable winds and biological feedback on hypoxic volume in Chesapeake Bay, which helps in the development of appropriate nutrient management strategies in a changing climate.