Human activities threaten fish habitats in riverine ecosystems all over the world. Dominant human stressors, however, differ regionally, with differences pronounced over large spatial extents. Consequently, anthropogenic impacts on fluvial fish habitats and thus on fish communities might also vary between continents. Based on the existing EFI+ (European Fish Index Plus) database for Europe and the NFHP (National Fish Habitat Partnership) database for the United States, a first detailed cross-continental analysis on the response of fish communities to large-scale human stressors, including land use, human population density, and road crossing density has been conducted. The joint database comprises over 30,000 fish sampling sites spread across 55 Freshwater Ecoregions of the World (FEOW). To characterize changes in fish communities caused by increasing intensity of human stressors, threshold analyses were performed for selected ecoregions across the two continents. This study highlights biogeographical differences and similarities between European and the United States fish communities and reveals new findings on influences of anthropogenic disturbances on river ecosystems, including dominant influences by regions. In addition, our results support international river basin management with better understanding of biogeographical processes in a human-dominated world towards future conservation and restoration of fish habitats on both continents.