Multi-year droughts are important and impactful features of California’s Mediterranean climate and can fundamentally affect the water quality and the ecosystem response of the San Francisco Estuary (Estuary) and the Sacramento-San Joaquin Delta (Delta). This study assesses data collected by long-term monitoring programs over the past 46 years (1975-2021) to evaluate how water quality in the Estuary changes during multi-year droughts. We found that multi-year droughts alter multiple physical and chemical parameters in the Estuary, increasing water temperature, salinity, water clarity, and nutrient levels. This trend was consistent across regions and seasons, with few exceptions. Increases in these parameters during droughts are likely caused by reduced Delta inflows that intensified in each successive dry year because of reduced precipitation and reservoir releases. Droughts did not substantially effect on tidal velocities within the Estuary, which remained mostly consistent across wet and dry periods. Trends in chlorophyll concentrations during droughts were more nuanced with higher concentrations occurring in the South-Central Delta region and during the winter and spring. Together, these results paint a picture of drought in the Estuary as warm, clear, high in nutrients, with patchy phytoplankton blooms (as indexed by chlorophyll), all of which have implications for higher trophic levels. Considering that droughts are expected to increase in frequency and intensity in California with climate change, it is imperative to understand the effects of multi-year droughts on the water quality conditions of the Estuary when making water management decisions.