Large carnivores are currently disappearing from many world regions because of habitat loss, prey depletion, and persecution. Ensuring large carnivore persistence requires safeguarding and sometimes facilitating the expansion of their populations. Understanding which conservation strategies, such as reducing persecution or restoring prey, are most effective to help carnivores to reclaim their former ranges is therefore important. Here, we systematically explored such alternative strategies for the endangered Persian leopard (Panthera pardus saxicolor) in the Caucasus. We combined a rule-based habitat suitability map and a spatially explicit leopard population model to identify potential leopard subpopulations (i.e., breeding patches), and to test the effect of different levels of persecution reduction and prey restoration on leopard population viability across the entire Caucasus ecoregion and northern Iran (about 737,000 km2). We identified substantial areas of potentially suitable leopard habitat (~120,000 km2), most of which is currently unoccupied. Our model revealed that leopards could potentially recolonize these patches and increase to a population of >1,000 individuals in 100 yr, but only in scenarios of medium to high persecution reduction and prey restoration. Overall, reducing persecution had a more pronounced effect on leopard metapopulation viability than prey restoration: Without conservation strategies to reduce persecution, leopards went extinct from the Caucasus in all scenarios tested. Our study highlights the importance of persecution reduction in small populations, which should hence be prioritized when resources for conservation are limited. We show how individual-based, spatially explicit metapopulation models can help in quantifying the recolonization potential of large carnivores in unoccupied habitat, designing adequate conservation strategies to foster such recolonizations, and anticipating the long-term prospects of carnivore populations under alternative scenarios. Our study also outlines how data scarcity, which is typical for threatened range-expanding species, can be overcome with a rule-based habitat map. For Persian leopards, our projections clearly suggest that there is a large potential for a viable metapopulation in the Caucasus, but only if major conservation actions are taken towards reducing persecution and restoring prey.