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A three‐dimensional unstructured‐grid hydrodynamic and water quality model (Semi‐implicit Cross‐scale Hydroscience Intergrated System Model‐Integrated Compartment Model) is applied successfully for Chesapeake Bay. The model is validated with observations of salinity, chlorophyll‐a, dissolved oxygen, nutrients, and phytoplankton productions from the year 1991 to 1995 for the mainstem and some major tributaries, based on multiple model skill scores. Model experiments are conducted to test the importance of having (1) an accurate representation of bathymetry to correctly predict hypoxia and other processes and (2) a high‐resolution model grid for tributaries to correctly simulate water quality variables. Comparison with the model experiment results with bathymetry smoothing indicates that bathymetry smoothing, as commonly used for many systems, changes the stratification and lateral circulation pattern, resulting in more salt intrusion into shallow water regions, and an increase in the freshwater age. Consequently, a model with bathymetry smoothing can lead to an unrealistic prediction of the distribution of hypoxia and phytoplankton production. Local grid refinement shows significant improvement of model simulations on local stratification and water quality variables. Overall, the use of high‐resolution unstructured grid model leads to a faithful representation of the complex geometry, and thus a seamless cross‐scale capability for simulating water quality processes in the Bay including tributaries and tidal creeks.