River communities are considered resilient to drought, but climate change is altering drought characteristics and interacts with human pressures, compromising long-term ecological recovery. Due to the unpredictability of drought events and the limited availability of long-term, large-scale ecological data, the drivers of community resistance and resilience to drought remain poorly understood. We used an unprecedented dataset spanning 359, 8–30-year time-series from groundwater-dominated river sites in England to characterize ecological responses to multiple droughts and interacting pressures. Our aims were to determine how 1) drought characteristics and human pressures, including flow alteration and water quality, interact to influence aquatic invertebrate community resistance and resilience to droughts, and 2) to identify drought-driven persistent shifts in community composition and their drivers. Although communities recovered on average within 1.5 years for 83% of droughts, those at 47% of sites experienced ≥1 long-term, drought-related compositional shift. However, shifts were as frequent during drought and non-drought periods, and pollution-sensitive taxa often characterized post-drought communities. Such results indicate that drought may reset communities, allowing sensitive taxa to take advantage of concurrent or independent improvements in habitat quality. Shifts in community composition increased with drought duration and decreased with frequency, and anthropogenic flow alteration and lower oxygen concentrations altered community resistance and resilience to drought. As drought severity increases in many global regions, our results could inform management actions that mitigate ecological impacts of future events in rivers exposed to multiple pressures.