Climate change is one of the key factors affecting the future quality and quantity of water in rivers and tidal estuaries. A coupled three-dimensional hydrodynamic and water quality model has been developed and applied to the Danshuei River estuarine system in northern Taiwan to predict the influences of climate change on water quality. The water quality model considers state variables including nitrogen, phosphorus, organic carbon, and phytoplankton as well as dissolved oxygen, and is driven by a three-dimensional hydrodynamic model. The hydrodynamic water quality model was validated with observational salinity distribution and water quality state variables. According to the analyses of statistical error, predictions of salinity, dissolved oxygen, and nutrients from the model simulation quantitatively agreed with the observed data. The validated model was then applied to predict water quality conditions as a result of projected climate change effects. The simulated results indicated that the dissolved oxygen concentration was projected to significantly decrease whereas nutrients will increase because of climate change. Moreover, the dissolved oxygen concentration was lower than 2 mg/L in the main stream of the Danshuei River estuary and failed to meet the water quality standard. An appropriate strategy for effective water quality management for tidal estuaries is needed given the projected persistent climate trends.