Punctuated, mass mortality events are increasing for many animal taxa and are often related to climatic extremes such as drought. Freshwater mussels are experiencing increased mass mortality events linked to hydrologic drought. Because mussels play important functional roles in rivers it is important to understand the ecosystem effects of these die-offs. Here, we address how mass mortality events of mussels caused by drought may impact stream ecosystem function. We first present a conceptual model, based on the literature, of how mussel mass mortality should affect different ecosystem functions across various ecological time scales, from hours to decades. Next, we highlight two case studies of drought-linked, mussel-mass mortality events from rivers in the southern U.S. We then present the results of an experiment we performed quantifying the ecosystem effects of a punctuated mussel die-off. Finally, we combine our experimental results with field data from a recent mussel die-off to predict how mussel losses will influence ecosystem function. Based on the presented case studies, our mesocosm experiment, and our extrapolated nutrient pulse due to a mussel die-off, we conclude that stream ecosystems are extensively altered following mussel mass mortality events. Mussel loss is governed by drought severity, location within the river network, and species-specific drought tolerances. In the short term, decomposing carrion from mussel die-offs releases a large pulse of nutrients into the water which stimulates food web productivity. In the long term, the overall loss of mussel biomass, and the loss of functional traits as more sensitive species decline, leads to decreases in ecosystem function which may take decades to recover. Drought and human demand for water will make mussel die-offs more likely in the future and it is unlikely that drought sensitive species will recover without changes in water management and restoration of populations through mussel propagation. Our research provides an example of how the loss of an abundant, long-lived organism has cascading and long-term impacts on ecosystems.