Desert rodents exhibit irruptive (boom–bust) population dynamics in response to pulses of primary productivity. Such unpredictable population dynamics are a challenge for monitoring population trends and managing populations, particularly for species in decline. We studied the population dynamics and occurrence of populations of the vulnerable plains mouse, Pseudomys australis (42-g body mass), during the low (bust) phase of the cycle in the Simpson Desert, Australia, to examine the use of refuges by the species and the predation pressure experienced from native and introduced predators. Specifically we investigated landscape-scale occurrence; body mass, reproduction, and population size; and presence of native and introduced predators. Our results demonstrate that P. australis contracted to discrete areas of the landscape (refuges) during the low phase and that these areas occupied a small proportion (∼17%) of the range occupied during population peaks. Animals in refuge populations had comparable body mass, occurred at similar densities to populations during the boom phase, and continued to reproduce during dry conditions. Such refuges represented a significant concentration of biomass to predators in a resource-poor environment. Native predators were rare during the low phase, suggesting that refuges naturally experienced low predation levels. Two introduced predators, feral house cats and red foxes, persisted during the low phase and exploited refuge populations of P. australis, thus representing a significant threat to population persistence. We advocate a novel approach to management of rodents in arid systems that involves identifying the discrete parts of the landscape that function as drought refuges and then focusing threat management there. The relatively small size of these refuges increases the likelihood of cost-effective management.