Protected areas form the cornerstone of global efforts to conserve biodiversity. Most current methods for designing reserve networks focus on maximizing the representation of species, but with no assurance that those species will persist in the protected landscapes into the future. We present a new strategy for reserve design that combines metapopulation theory with spatial conservation prioritization to estimate conservation solutions that minimize extinction risk across numerous species simultaneously. Our framework optimizes the spatial configuration of reserves to maximize metapopulation persistence for an entire assemblage of species by accounting for both species representation and landscape connectivity. As a case study, we design a reserve network for 114 terrestrial mammal species in Indonesian New Guinea. Our approach builds on Marxan, the flagship representation-based reserve design tool, improving estimated persistence (metapopulation capacity) by an average of 4.6-fold across species, without increasing the socioeconomic cost. We suggest that enhancing species persistence, rather than protecting arbitrary proportions of species' ranges, should be the ultimate objective of conservation planning.