We predicted future plague and black-tailed prairie dog dynamics in the North American prairies under different scenarios of climate change. A climate-driven model for the joint dynamic of the host–parasite system was used. Projections for the regional climate were obtained through empirical–statistical downscaling of global climate scenarios generated by an ensemble of global climate models for the recent Fourth Assessment Report by the IPCC. The study shows the uncertainties involved in predicting future regional climate and climate-driven population dynamics, but reveals that unchanged or lower levels of plague, leading to increased black-tailed prairie dog colonies, can be expected. Less plague is particularly expected for scenarios that assume the highest emission of greenhouse gases associated with the greatest projected future warming. Moreover, under high-emission scenarios, decreased probabilities of extremely high numbers of infected colonies are expected, along with decreased probabilities of extremely low total numbers of colonies. The assumed main underlying mechanism is an inhibiting effect of high temperatures on fleas (dispersal vector) and on flea-mediated transmission of the disease-causing bacterium. Our study highlights the importance of using dynamic ecological (here host–parasite) models together with ensembles of climate projections to investigate the responses of populations and parasites to a changed climate.