These data were collected for the special issue on Drought in the Sacramento-San Joaquin Delta published in San Francisco Estuary and Watershed Sciences, Volume 22, Issue 1, March of 2024. 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 and the Sacramento-San Joaquin Delta. This data set was assembled from data collected by long-term monitoring programs over the past 46 years (1975-2021) to evaluate how the estuary changed during multi-year droughts. Data include fish, zooplankton, jellyfish, clams, temperature, Secchi depth, and salinity as measured by fish and water quality surveys, as well as nutrients and chlorophyll measured by water quality surveys. These data are accompanied by hydrologic metrics including Delta Inflow, Delta Outflow, the position of the 2-PSU isohaline, and residence time, and daily values of various continuous water quality stations located in the Delta.