Microbial ecology studies have proven to be important resources for improving infectious disease response and outbreak prevention. Vibrio parahaemolyticus is an ongoing source of shellfish-borne food illness in the Northeast, United States and there is keen interest in understanding the environmental conditions that coincide with V. parahaemolyticus disease risk to aid harvest management and prevent further illness. Zooplankton and chitinous phytoplankton associate with V. parahaemolyticus dynamics elsewhere, however, this relationship is undetermined for the Great Bay estuary (GBE), an important emerging shellfish growing region in the Northeast, US. A comprehensive evaluation of the microbial ecology of V. parahaemolyticus associated with plankton was conducted in the GBE using three years of plankton community, nutrient concentration, water quality and V. parahaemolyticus concentration in plankton data. The concentrations of V. parahaemolyticus associated with plankton were highly seasonal and the highest concentrations of V. parahaemolyticus cultured from zooplankton occurred approximately one month before the highest concentrations of V. parahaemolyticus from phytoplankton. The two V. parahaemolyticus peaks corresponded with different water quality variables and a few highly seasonal plankton taxa. Importantly, V. parahaemolyticus concentrations and plankton community dynamics were poorly associated with nutrient concentrations and chlorophyll-a, commonly applied proxy variables for assessing ecological health risks, and human health risks from harmful plankton and V. parahaemolyticus elsewhere. Together, these statistical associations (or lack thereof) provide valuable insights to characterize the plankton-V. parahaemolyticus dynamic and inform approaches for understanding the potential contribution of plankton to human health risks from V. parahaemolyticus for the Northeast US. IMPORTANCE The Vibrio-plankton interaction is a focal relationship in Vibrio disease research; however, little is known about this dynamic in the Northeast, US where V. parahaemolyticus is an established public health issue. We integrated phototactic plankton separation with seasonality analysis to determine the dynamics of the plankton community, water quality and V. parahaemolyticus concentrations. Distinct bimodal peaks in the seasonal timing of V. parahaemolyticus abundance from phyto- vs zooplankton and differing associations with water quality variables and plankton taxa highlight that monitoring and forecasting approaches should consider the source of exposure when designing predictive methods for V. parahaemolyticus. Heliotheca tamensis has not been previously reported in the GBE. Its detection during this study provides evidence of the changes occurring in the ecology of regional estuaries and potential mechanisms for changes in V. parahaemolyticus populations. The Vibrio monitoring approaches can be translated to aid other areas facing similar public health challenges.