BackgroundCoral reefs have exceptional biodiversity, support the livelihoods of millions of people, and are threatened by multiple human activities on land (e.g. farming) and in the sea (e.g. overfishing). Most conservation efforts occur at local scales and, when effective, can increase the resilience of coral reefs to global threats such as climate change (e.g. warming water and ocean acidification). Limited resources for conservation require that we efficiently prioritize where and how to best sustain coral reef ecosystems.Methodology/principal findingsHere we develop the first prioritization approach that can guide regional-scale conservation investments in land- and sea-based conservation actions that cost-effectively mitigate threats to coral reefs, and apply it to the Coral Triangle, an area of significant global attention and funding. Using information on threats to marine ecosystems, effectiveness of management actions at abating threats, and the management and opportunity costs of actions, we calculate the rate of return on investment in two conservation actions in sixteen ecoregions. We discover that marine conservation almost always trumps terrestrial conservation within any ecoregion, but terrestrial conservation in one ecoregion can be a better investment than marine conservation in another. We show how these results could be used to allocate a limited budget for conservation and compare them to priorities based on individual criteria.Conclusions/significancePrevious prioritization approaches do not consider both land and sea-based threats or the socioeconomic costs of conserving coral reefs. A simple and transparent approach like ours is essential to support effective coral reef conservation decisions in a large and diverse region like the Coral Triangle, but can be applied at any scale and to other marine ecosystems.