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As global change intensifies, species are increasingly affected by multiple co-occurring threats. Determining how co-occurring threats interact is crucial for understanding decline trajectories and guiding effective management responses. We used dynamic occupancy models fitted to two decades of monitoring data for the Growling Grass Frog (Litoria raniformis) in southeastern Australia to examine the combined effects of two prominent global threats to amphibians: urbanization and the disease chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd). Site occupancy declined by 38% during the study period. Occupancy modeling demonstrated that the probability of persistence was substantially lower at sites with a high estimated prevalence of Bd infections, and that populations disconnected from neighbors by urban barriers had both a lower probability of persistence and a lower probability of being recolonized following local extinction. Population persistence was also associated with diverse aquatic vegetation communities, which are typically degraded by urbanization. We used simulations to investigate the individual and combined impacts of chytridiomycosis and urbanization on equilibrium occupancy rates in the study area, and to determine how these threats interact. These simulations revealed that chytridiomycosis has a larger impact on occupancy dynamics than urbanization, but the combined impact of these two threats is more severe than their individual impacts would suggest. Equilibrium occupancy was substantially higher than observed rates when Bd impacts were removed (even with urbanization included), whereas equilibrium occupancy under a scenario of ongoing Bd impacts but no urbanization was close to occupancy at the start of the study. Including both threats (Bd plus urbanization) reduced equilibrium occupancy by 69%, and there was evidence for synergistic effects-the joint impact of these threats was greater than the sum of their individual impacts in ~80% of simulations. This study-combining long-term monitoring, detailed statistical modeling, and metapopulation simulations-suggests that interactions between disease and other threatening processes are important drivers of amphibian declines and provides insights into the underlying ecological mechanisms. More broadly, our results add weight to concerns about interactions between threats under global change, emphasizing the need for comprehensive assessments of the impact of co-occurring threats to better target management actions.