Human stressors are currently impacting both the Amazon and Orinoco river basins and these are likely to increase. However, there is a lack of standardized monitoring programs to track these human stressors in most of the countries that overlap these basins, and no clear ecological indicators have been identified. In this study we investigated the relationships between measures of ecosystem degradation and river dolphins as potential ecological indicators. The presence of human stressors and their distance from the areas surveyed were used to provide an estimate of ecosystem degradation. We tested three ecological indicators of freshwater ecosystem degradation using river dolphins: (i) density of river dolphins, (ii) mean group size of dolphins, and (iii) dolphin sighting rates. We found a strong negative relationship between measures of habitat degradation and river dolphin density estimates in selected locations of the Amazon and Orinoco. Therefore, we suggest that river dolphins are good candidates as ecological indicators, flagship and sentinel species for monitoring the conservation status of large tropical rivers in South America. We suggest that further effort should be directed toward collecting reliable data on human stressors, creating collaborative networks for compiling existing data, and documenting and monitoring current trends in freshwater ecosystem degradation and indicator species in the Amazon and Orinoco basins with the goal of targeting areas for recovery or sustainable management.