Droughts have major effects on estuaries because freshwater entry is one of the defining features of an estuary, and freshwater flow is an important variable that determines the interannual change in the environment. In the upper San Francisco Estuary (the Sacramento–San Joaquin Delta, Suisun Bay, and Suisun Marsh), the Mediterranean climate includes frequent multi-year droughts. To assess ecosystem responses to droughts in the upper estuary, the Interagency Ecological Program Drought Synthesis Team assembled a set of flow, water quality, chlorophyll, zooplankton, and fish data from 1975 to 2021 to test for differences between multi-year droughts and multi-year wet periods and tested for linear relationships between each variable and the Sacramento Valley Hydrologic Index (see definitions and relationships as outlined in Appendix A). Our models showed droughts decreased Delta outflow, project exports, zooplankton in Suisun Bay, and some fish species. We also found that droughts increased water clarity, salinity, nutrients, chlorophyll in the South Delta, zooplankton in the South Delta, and water residence time. Although our analyses only tested correlations, we hypothesized that most of the food-web responses could be traced to increased residence time, decreased transport rates, or both. However, some responses may have been caused by secondary effects, including shifts in salinity gradients, regional changes in water quality, or differences in top-down effects of increased predation and grazing rates. With increased frequency of droughts in the future, this increasingly low-outflow, warming, clearing estuary—which is invaded by non-native species and has low pelagic fish production—is rapidly becoming the new “normal.”