Water temperature and inflow are key environmental drivers in aquatic systems that are linked through a causal web of factors including climate, weather, water management, and their downstream linkages. However, we do not yet fully understand the relationship between inflow and water temperature, especially in complex managed systems such as estuaries. The San Francisco Estuary is the center of a critical water supply infrastructure and home to a deteriorating ecosystem with several declining fish species at the warm edge of their thermal range. We used generalized additive modeling of long-term monitoring data to evaluate the relationship between inflow and water temperature along with its spatio-seasonal variability. Most commonly, we found a negative temperature-inflow relationship in which water temperatures increased as inflow decreased, up to 2 °C from high to low-inflow years. However, the opposite (positive) relationship was observed in the winter months, and in the western (downstream) regions from July-September, up to -1.2 °C from high to low-inflow years. These results were upheld by models that included the long-term temperature trend or used salinity as a proxy for location. Upstream factors likely played the biggest role in the summer when local precipitation is negligible, whereas local precipitation and the related weather conditions may drive much of the winter pattern. Although further mechanistic studies are needed to infer the direct effect of dam releases on water temperatures, these results provide a broader understanding of the impacts of flood and drought dynamics for those tasked with managing estuarine ecosystems.