Seasonal and interannual variations of freshwater flow strongly influence estuarine processes, exemplified by plankton biomass and productivity. The main tributary feeding Chesapeake Bay, the Susquehanna River, has shown threefold variability of spring flow in the last 52 years. The magnitude of spring discharge from the Susquehanna River is associated with the frequency and type of weather patterns transiting the eastern United States during winter and is related to the precipitation stored in the basin as snow and ice. Large-scale indices of climate variability, such as El Niño–Southern Oscillation and the North Atlantic Oscillation, have not proven to be strong predictors of freshwater flow in the Mid-Atlantic. We developed a synoptic climatology as an alternative way to quantify and classify regional weather, focusing on the types and frequency of occurrence of patterns we identified for winter. This approach was used to predict freshwater flow in spring and explained 54% of the variance of spring discharge after extreme outliers were removed. Responses of Chesapeake Bay plankton to contrasting years of weather pattern frequencies and associated freshwater flow were examined to illustrate ecosystem response to climatic forcing.