Here, this is tested by building and implementing a new dynamical-statistical hydroclimatic ensemble prediction system. Dynamical modeling is used to generate S2S flow predictions, which are then combined with quantile regression to generate water quality forecasts. The system is forced with the latest S2S climate forecasts from the National Oceanic and Atmospheric Administration’s Climate Forecast System version 2 to generate biweekly flow, and monthly total nitrogen, total phosphorus, and total suspended sediment loads. By implementing the system along a major tributary of the Chesapeake Bay, the largest estuary in the US, we demonstrate that the dynamical-statistical approach generates skillful flow, nutrient load, and suspended sediment load forecasts at lead times of 1–3 months. Through the dynamical-statistical approach, the system comprises a cost and time effective solution to operational S2S water quality prediction.