Mexico is a biologically megadiverse country, but its biodiversity is endangered due to high deforestation rates. Impacts of land-use/cover-change and climate change are unevenly distributed, which hinders the execution of conservation practices. Consequently, an adequate spatial conservation prioritization is crucial to minimize the negative impacts on biodiversity. Global and national efforts to prioritize conservation show that >45% of Mexico should be protected. This study develops an applicable spatial conservation prioritization to minimize impacts on biodiversity, under three scenarios. They integrate exposure to land-use/cover-change and climate change scenarios, adaptive capacity to deal with the exposure, and the distribution of endemic species on risk of extinction. Our results show that by 2050 between 11.6%, 13.9% and 16.1% of Mexico would reach score ≥50 in vulnerability (VI), under the optimistic, BAU, and the worst-case scenarios, respectively. By 2070, these figures would rise to 11.9%, 14.8% and 18.4%. Amphibians are the most threatened vertebrates with 62.2% of endemic species being critically endangered or endangered, while 39.2%, 11.8%, and 8.5% of endemic mammals, birds and reptiles are endangered or critically endangered. The distribution of these amphibians accounts for 3.3% of the country's area, while mammals, birds, and reptiles represent 9.9%, 16.2%, and 28.7% of Mexico. Moreover, seven municipalities (0.39% of the country) represent 30% of the most vulnerable areas (VI=70). This study offers relevant information at the levels of municipality and species to help decision-makers prioritize national efforts for the conservation of ecosystems and biodiversity under land-use/cover and climate change. This study is replicable in other regions which aim to adapt decision-making and land management for biodiversity conservation.