Drought and nutrient pollution can affect the dynamics of stream ecosystems in diverse ways. While the individual effects of both stressors are broadly examined in the literature, we still know relatively little about if and how these stressors interact. Here, we performed a mesocosm experiment that explores the compounded effects of seasonal drought via water withdrawals and nutrient pollution (1.0 mg/L of N and 0.1 mg/L of P) on a subset of Ozark stream community fauna and ecosystem processes. We observed biological responses to individual stressors as well as both additive and antagonistic stressor interactions. We found that drying negatively affected periphyton assemblages, macroinvertebrate colonization, and leaf litter decomposition in shallow habitats. However, in deep habitats, drought-based concentration effects caused trophic cascades that released algal communities from grazing pressures; while nutrient enrichment caused bottom-up cascades that influenced periphyton variables and crayfish growth rates. Finally, the combined effects of drought and nutrient enrichment interacted antagonistically to increase survival in longear sunfish; and stressors acted synergistically on grazers causing a trophic cascade that increased periphyton variables. Because stressors can differentially impact biota—and that the same stressor pairing can act both additively and antagonistically on different portions of the community simultaneously—our broad understanding of individual stressors might not adequately inform our knowledge of multi-stressor systems.