Climate change is predicted to place up to one in six species at risk of extinction in coming decades, but extinction probability is likely to be influenced further by biotic interactions such as predation. We use structural equation modelling to integrate results from remote camera trapping and long-term (17–22 years) regional-scale (8000 km2) datasets on vegetation and small vertebrates (greater than 38 880 captures) to explore how biotic processes and two key abiotic drivers influence the structure of a diverse assemblage of desert biota in central Australia. We use our models to predict how changes in rainfall and wildfire are likely to influence the cover and productivity of the dominant vegetation and the impacts of predators on their primary rodent prey over a 100-year timeframe. Our results show that, while vegetation cover may decline due to climate change, the strongest negative effect on prey populations in this desert system is top-down suppression from introduced predators.