Climate projections and their effects in the San Francisco Estuary have been evaluated as part of the US Geological Survey’s CASCaDE2 project. Understanding the ecological effects of climate change can help manage and maintain the ecological health and productivity of the San Francisco Estuary. In this study, we assessed downscaled air temperature data from 10 global climate models (GCMs) under two representative concentration pathway (RCP) trajectories for greenhouse gas concentrations for three regions of the San Francisco Estuary: Sacramento–San Joaquin Delta, Suisun and Grizzly bays, and Suisun Marsh. We also used previously derived regression models to estimate future water temperatures at 16 locations in the upper San Francisco Estuary. We used a thermal regime approach to summarize water temperature projections to investigate changes to the thermal regime of the upper San Francisco Estuary, and used the Delta Smelt (Hypomesus transpacificus) to demonstrate the effects that a warming climate may have on the habitat needs of this fish species. Our results suggested there were no major differences in the extent of air-temperature warming among the three regions. Annual average air temperatures were projected to increase approximately 2.0 °C and 4.7 °C by the end of the century for the low and high RCP scenarios, respectively. We found timing, frequency, and magnitude metrics varied by period and RCP scenario, while duration and variability metrics varied by space for water-temperature thermal regimes. For example, the spawning window for Delta Smelt (thermal-regime duration metric) is projected to expand in the future, with spawning starting earlier for both RCP scenarios for most sites. Although our thermal-regime analysis focused on the life history of Delta Smelt, similar approaches could be used to assess climate-change threats to a wide array of native and invasive terrestrial and aquatic species found in San Francisco Estuary.