In the current world of diminished economic resources, environmental conservation activities must continue to become more efficient and effective. This reality has fueled research to improve conservation priority setting, where recent advances have focused on explicitly incorporating the economic costs of conservation along with better defining the outcomes of these expenditures. We demonstrate how new global and continental data that spans social, economic, and ecological sectors creates an opportunity to incorporate return-on-investment (ROI) principles into conservation priority setting for Africa. We suggest that combining priorities across terrestrial, freshwater, and coastal marine environments provides a new lens for setting global conservation priorities that may identify areas of important ecosystem service benefits to society. We illustrate how spatially explicit, yet flexible ROI analysis can help to better address uncertainty, risk, and opportunities. Given the need to improve conservation in light of decreasing resources and increasing urgency due to climate change, we propose that adopting a flexible ROI framework to set conservation priorities in Africa conservation has multiple benefits.