The Indus basin heavily depends on its upstream mountainous part for the downstream supply of water while downstream demands are high. Since downstream demands will likely continue to increase, accurate hydrological projections for the future supply are important. We use an ensemble of statistically downscaled CMIP5 General Circulation Model outputs for RCP4.5 and RCP8.5 to force a cryospheric hydrological model and generate transient hydrological projections for the entire 21st century for the upper Indus basin. Three methodological advances are introduced: (i) A new precipitation dataset that corrects for the underestimation of high-altitude precipitation is used. (ii) The model is calibrated using data on river runoff, snow cover and geodetic glacier mass balance. (iii) An advanced statistical downscaling technique is used that accounts for changes in precipitation extremes. The analysis of the results focuses on changes in sources of runoff, seasonality and hydrological extremes. We conclude that the future of the upper Indus basin’s water availability is highly uncertain in the long run, mainly due to the large spread in the future precipitation projections. Despite large uncertainties in the future climate and long-term water availability, basin-wide patterns and trends of seasonal shifts in water availability are consistent across climate change scenarios. Most prominent is the attenuation of the annual hydrograph and shift from summer peak flow towards the other seasons for most ensemble members. In addition there are distinct spatial patterns in the response that relate to monsoon influence and the importance of meltwater. Analysis of future hydrological extremes reveals that increases in intensity and frequency of extreme discharges are very likely for most of the upper Indus basin and most ensemble members.