Study region: Santa River basin, Peru. Study focus: In the Andes of Peru, climate change and socio-economic development are expected to jeopardize future water availability. However, little is known about the interplay of multiple climatic and non-climatic stressors and related processes driving water resource changes. We developed an integrated model that analyzes different trajectories of water availability including hydro-climatic (water supply) and socio-economic (water demand) variables with consistent multi-descriptor future scenarios until 2050. New hydrological insights for the region: At the lower-basin outflow of Condorcerro, mean annual water availability is projected to increase by 10% ± 12% by 2050. This gain is mainly driven by an increase in annual precipitation amounts of about 14% (RCP2.6) and 18% (RCP8.5), respectively, which was computed using a global climate multi-model ensemble. In contrast, mean dry-season water availability is projected to substantially decrease by 33% and 36% ( ± 24%) by 2050, for RCP2.6 and RCP8.5, respectively. This decline is driven by a combination of diminishing glacier discharge and increasing water demand both of which adopt a major role in the absence of considerable precipitation inputs. These seasonal differences highlight the need to adequately consider spatiotemporal scales within multi-scenario water balance models to support local decision-making. Our results elucidate the need for improvements in water management and infrastructure to counteract diminishing dry-season water availability and to reduce future risks of water scarcity.