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. Climate is a major abiotic driver for dryland species; the Australian central desert regions especially are not immune from climate change, with higher temperatures and an increase in the frequency and magnitude of extreme rainfall events already recorded over the last 100 years. Wildfire return intervals are also predicted to decrease due to climate change, making it imperative that we understand how both biotic and abiotic interactions shape ecological systems. Here we use structural equation modelling to integrate results from remote camera trapping and long-term (17–22 years) regional-scale (8,000 km2) datasets for vegetation and small vertebrates (>38,880 captures) to explore how biotic processes and two key abiotic drivers influence the structure of a diverse assemblage of desert biota. Our models are used 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 will decline due to climate change, the primary influence on prey populations is top-down suppression. Introduced predators have the strongest negative effects on prey.