1. As ecosystems experience simultaneous disturbances, it is critical to understand how multiple stressors interact to affect ecological change. Land-use change (LUC) and extreme flow events are two important stressors that could interact to affect fish populations. 2. We evaluated the individual and interactive effects of discharge and LUC associated with oil and natural gas development (ONGD) on populations of two stream fishes over a seven-year period. We used repeated-state (i.e., abundance trends) and rate (i.e., colonization and persistence) responses to advance our understanding of flow-ecology relationships in a multiple-stressor framework. 3. Overall, fish abundance, colonization, and persistence declined in association with discharge. The effect of LUC associated with ONGD differed between species, with the abundance of Mottled Sculpin declining and Mountain Sucker increasing. We found both synergistic and antagonistic interactions between discharge and LUC. LUC intensified the effect of low flows for one species and lead to greater variability in responses to flows for the other species. These differences between species’ responses are likely due to differences in their physiological tolerances and behavioral adaptations to disturbance. 4. Synthesis and applications. Our research provides empirical evidence for the complex interactions that can arise between discharge and anthropogenic LUC. Management efforts (e.g., silt fences, vegetation replanting, and in-stream restoration) to mitigate the effects of anthropogenic alterations and promote high-quality refuge habitats could help mitigate the effect of hydrologic extremes. Further development of flow-ecology relationships in a multiple-stressor framework will help guide management of stream fishes, and provide a better understanding of the mechanisms underlying flow-ecology relationships for different species.06-Sep-2019