The world's large terrestrial mammalian carnivores and herbivores (henceforth, megafauna) has been severely impacted by humans worldwide. Although this impact across the globe is variable, there has been little information quantifying this impact on biodiversity. Here, we use a macroecological modeling approach to evaluate the impact of different human activities on megafauna species richness at global and biogeographical scales with respect to seven human-altered landscapes variables. At both global and biogeographical scales, we found that human accessibility, human footprint, and small livestock density, had the most negative effects on megafauna species richness, whereas large livestock density, wilderness, and natural protected areas, were more positively associated with megafauna species richness. Our results indicate that megafauna can indeed persist in human-modified landscapes, but different types of human activity can differentially influence species richness. Thus, although continued human impact such as urban, livestock and agricultural development continues to represent a threat to most megafauna, their future viability is potentially compatible with several global change factors we examined. Moreover, our findings are still consistent with the emphasis on conservation strategies that focus on habitat protection to maximize the conservation of megafaunal richness. We urge stronger national and international policy commitments inclusive of multi-use landscapes, greater anti-poaching enforcement, and the development of wildlife-friendly policy incentives for the managers of private and communal land. We also advise caution in interpreting our results, and believe local and regional scale population monitoring programs are still necessary to better facilitate coexistence with humans.