The Sonoran Desert and Apache Highlands ecoregions of North America are areas of exceptionally high plant and vertebrate biodiversity. However, much of the vertebrate biodiversity is supported by only a few vegetation types with limited distributions, some of which are increasingly threatened by changing land uses. We assessed the impacts of two future urban growth scenarios on biodiversity in a binational watershed in Arizona, USA and Sonora, Mexico. We quantified and mapped terrestrial vertebrate species richness using Wildlife Habitat Relation models and validated the results with data from National Park Service biological inventories. Future urban growth, based on historical trends, was projected to the year 2050 for 1) a “Current Trends” scenario and, 2) a “Megalopolis” scenario that represented a transnational growth corridor with open-space conservation attributes. Based on Current Trends, 45% of existing riparian woodland (267 of 451species), and 34% of semi-desert grasslands (215 of 451 species) will be lost, whereas, in the Megalopolis scenario, these types would decline by 44% and 24% respectively. Outcomes of the two models suggest a trade-off at the taxonomic class level: Current Trends would reduce and fragment mammal and herpetofauna habitat, while Megalopolis would result in loss of avian-rich riparian habitat.