Excessive nutrient loading is a well-established driver of hypoxia in aquatic ecosystems. However, recent limnological research has illuminated the role of Chromophoric Dissolved Organic Matter (CDOM) in exacerbating hypoxic conditions, particularly in freshwater lakes. In coastal ocean environments, the influence of CDOM on hypoxia remains an underexplored area of investigation. This study seeks to elucidate the intricate relationship between CDOM and hypoxia by employing a nitrogen-based model within the context of Chesapeake Bay, a large estuary with unique characteristics including salinity stratification and the localization of hypoxia/anoxia in a 30-meter-deep channel aligned with the estuary’s primary stem. Our findings indicate that the impact of CDOM on nutrient dynamics and productivity varies significantly across different regions of Chesapeake Bay. In the upper Bay, the removal of CDOM reduces light limitation, thus promoting increased productivity, resulting in the generation of more detritus and burial, which, in turn, contributes to elevated levels of hypoxia. As we transition to the middle and lower Bay, the removal of CDOM can cause a decline in integrated primary productivity due to nutrient uptake in the upper Bay. This decrease in productivity is associated with reduced burial and denitrification, ultimately leading to a decrease in hypoxia levels. Streamflow modulates this impact. The time integral of the hypoxic volume during low-flow years is particularly sensitive to CDOM removal, while in high-flow years, it is relatively unchanged. This research underscores the necessity for a comprehensive understanding of the intricate interactions between CDOM and hypoxia in coastal ecosystems.