In the Simpson Desert, central Australia, heavy rainfalls associated with the La Niña phase of the El Niño Southern Oscillation (ENSO) during 1999–2000 stimulated a pulse of primary productivity that prompted a rodent irruption during 2001, and subsequently an extensive wildfire in 2001–2002. More than 10,000 km² of spinifex habitat were burned. In this study we examine a time series of climatic variables, and small mammal and predator dynamics in the desert in 1999–2002; and a before–after–control-impact study investigating the effects of the wildfire on small mammals. Rodents showed a delayed numerical increase in response to rainfall, whereas terrestrial predators showed a delayed numerical increase in response to rodent density. These delayed responses suggest the existence of bottom-up trophic pathways. However, a reduction in primary productivity and increase in predators appeared to suppress rodent numbers in 2001–2002, indicating that bottom-up effects can be temporarily reversed in this system. Wildfire had negative impacts on the abundance of the desert mouse (Pseudomys desertor) and the overall richness of small mammal species. Several other species of small mammals also appeared to show brief negative responses to wildfire. The impacts of wildfire on small mammals appear attributable to a loss of habitat for spinifex-dependent species and increased exposure to predation in burned habitats. Because extensive wildfires can be predicted from patterns of rainfall and fuel accumulation, we recommend that land managers be proactive in recognizing and reducing conditions of fire hazard. We recommend that small-scale prescribed burns should be carried out to reduce the extent of wildfires and also increase the chance of maintaining potential refuges from predators. In addition, control of introduced predators during and after irruptions of rodents will be crucial to prevent predator-driven crashes of their populations and those of secondary prey species. ENSO-related climatic forecasts appear to be useful cues that can be incorporated into fire and predator management strategies in arid Australia.