Invasive non-native species (INS) continue to pose a significant threat to biodiversity, including native population declines, which can ultimately disrupt ecosystem processes. Although there is growing evidence of the impacts of INS on functional diversity, most of the existing approaches to prioritization of species for conservation still focus on taxonomic diversity, neglecting the ecological role of species. We developed the functionally unique, specialized, and endangered by invasive non-native species (FUSE INS) score to fill this gap by combining functional irreplaceability (i.e., uniqueness and specialization) of species with their extinction risk due to INS. We calculated this score for 3642 terrestrial vertebrates exposed to INS by assessing how INS affected them based on the IUCN Red List and by evaluating their specialization and uniqueness in a multidimensional functional space. Thirty-eight percent of native species were both at high extinction risk because of INS and functionally unique and specialized, making them priority species for INS impact mitigation. Priority species of amphibians concentrated in Central America and Madagascar and of lizards in the Caribbean islands, northern Australia, New Zealand, and New Caledonia. Priority bird and mammal species were more widespread (birds, mostly in coastal areas, on Pacific islands, and in northern India and New Zealand; mammals, in southwestern Europe, Central Africa, East Africa, Southern Africa, Southeast Asia, and eastern Australia). Seventy-eight species were also highly irreplaceable but not yet threatened by INS, suggesting that preventive conservation measures may help protect these species. For the 50 birds of the highest priority, 64% required conservation actions to mitigate the INS threat. The FUSE INS score can be used to help prioritize indigenous species representing large amounts of functional diversity. Incorporating functional diversity into the conservation prioritization of species and associated areas is key to accurately reducing and mitigating the impacts of INS on native biodiversity.