Climate and land use change can affect biodiversity in different ways, e.g., determining habitat loss, altering reproduction periods or disrupting biotic interactions. Here, we investigate the effects of climate and land use change on the spatial distribution of two semi-aquatic mammals, the Pyrenean desman (Galemys pyrenaicus) and the Eurasian otter (Lutra lutra). We first modeled the current potential distribution of the desman and the otter in the Iberian Peninsula, considering topographic, climatic and land use variables. Second, we predicted their potential distribution in 2050 under climate and land use change scenarios. We calculated the percentage of range gain/loss and shift predicted for the two species under such scenarios and quantified the present and future spatial overlap between the two species distribution. Irrespective of the scenario, desman models show loss of suitable habitat, whereas the otter will undergo an opposite trend. Aside from a preponderant habitat loss, the desman is predicted to increase its spatial overlap with otter range under the optimistic scenarios, potentially meaning it will face an exacerbated predation by otters. The potential increase of both habitat loss and otters’ predation might represent a major threat for the desman, which may affect the long-term persistence of this endemic species in the Iberian Peninsula.