Scenario analysis has the potential to improve management of aquatic systems throughout the Mountaintop Removal–Valley Fill mining (MTR–VF) region of central Appalachia. However, the extent to which surface mining interacts with other landuse stressors (i.e., cumulative effects) is unclear, and this limits our ability to predict the effects of new mines on physical, chemical, and biological conditions downstream. We tested for additive and interactive effects of landuse change (surface mining, deep mining, and residential development) on water quality (specific conductance and Se), habitat quality, and benthic macroinvertebrates via a uniquely designed watershed-scale assessment of the Coal River, West Virginia (USA). We derived equations for predicting in-stream response to landscape changes and predicted the outcome of a realistic future scenario involving development of 15 permitted mines. Elevated Se concentrations were directly correlated with incremental increases in surface-mining extent. Surface mining, deep mining, and residential development had additive effects on elevated specific conductance and reduced biological condition. We found evidence of a positive interactive effect (stressor antagonism) of deep mining and residential development on biological condition, presumably caused by stream-flow augmentation from deep mines. Landscape context influenced predicted impacts from construction of 15 new mines because of additive and interactive effects of landuse change. New surface mines increased the number of receiving streams exceeding chemical and biological criteria, but a greater proportion of receiving streams exceeded chemical and biological criteria at equivalent levels of new mine development when pre-existing stressors were present. When surface mining was the only stressor, ≥30 or 40% increases in surface mining caused 100% of streams to exceed chemical or biological standards, respectively, whereas in streams stressed by deep mining and residential development, ≥10% additional surface mining caused 100% of streams to exceed chemical and biological standards. Continued progress in this area will require a better understanding of how landuse change affects aquatic systems in the rest of the MTR–VF mining region, where watershed-to-watershed variation in landuse patterns probably causes variability in ecological response.