- Predator outbreaks are predicted to increasingly decimate economically and ecologically important prey populations because global climate change and food-web modifications frequently facilitate predators and stress prey. Natural systems are organized hierarchically, with processes operating at multiple scales giving rise to patterns of biodiversity, so predicting and managing outbreaks requires a framework that accounts for the effects of both local and regional stressors. Here, we used the comparative experimental approach to investigate whether the collapse of a nationally important oyster fishery in the Gulf of Mexico (Apalachicola Bay, Florida) could have been (1) caused proximally by a predator outbreak and (2) whether this outbreak was mediated by local-and/or regional-scale forces. During the fishery collapse, we paired experiments with monitoring in Apalachicola Bay and found elevated water salinity, high abundance of predatory snails, and intense oyster mortality due to predation. By repeating these experiments over 4 yr, we found that periods of reduced water salinity inhibited predation on oysters. To partition the influence of local-versus-regional factors on this predator outbreak, we simultaneously replicated the paired experiments and monitoring in a nearby bay (Ochlockonee Bay) that shares the same regional-scale rainfall conditions. Increasing freshwater withdrawals from the watershed that drains into Apalachicola Bay have increased salinities in that bay, but there have not been similar withdrawals in the Ochlockonee Bay watershed. Therefore, Apalachicola Bay experienced a localized anthropogenic stress, while both bays experienced regional stress from drought. In Ochlockonee Bay, our experiments demonstrated that the river maintained sufficiently low salinity to provide similar to 50% of oyster reefs with a refuge from predation. In contrast, salinity-dependent predation in Apalachicola Bay extended up to the river mouth. Given the stark differences in upstream water withdrawals between these watersheds, it is reasonable to surmise that these withdrawals exacerbated the stress of regional drought, created the difference in predation between the two bays, and thus may have precipitated the oyster fishery collapse. Our study provides empirical support for recent theory about the hierarchical organization of ecosystems, which predicts that stressors will interact across scales to cause localized predator outbreaks.