The quantitative assessment of glacier changes and freshwater availability under future climate change is inevitable for sustainable water resources management and preventing natural disasters. Limiting the uncertainties in glacio-hydrological modeling and exploring spatiotemporal distributions of runoff and its components along the vertical profile are critical for such investigations. The present study quantifies glacio-hydrological changes using the Spatial Processes in HYdrology (SPHY) model forced by CMIP6 climate data (shared socioeconomic pathways: SSP126, SSP245, and SSP585) in the Upper Indus Basin (UIB) over twenty-first century. The model was calibrated based on in situ glacier changes, snow cover changes, and streamflow records to avoid the risk of equifinality. Variations in vertical distribution of runoff components and their impact on glacio-hydrology were investigated using the critical zone approach. The projected remaining glacier area is 55 ± 10%, 32 ± 17%, and 15 ± 5%, and freshwater availability is reduced by − 12 ± 5%, − 30 ± 7%, and − 36 ± 6% in 2100, compared with 2005-2014, under SSP126, SSP245, and SSP585, respectively. The average changes in snowmelt, glacier melt, baseflow, and rain-runoff contributions to total runoff under SSP245 are projected as 25 ± 15%, − 30 ± 11%, − 20 ± 16%, and 242 ± 71%, respectively. The critical zone (3500 - 5500 masl) contributes 63% of total runoff during the reference period, with a significant reduction (51-81%) in the projected period, indicating a diminishing influence of glacier runoff (with 50% reduction) in future hydrology compared with historical period. In turn, low flows (October-March) are projected to increase (9 − 58%), and high flows (April-September) will likely decrease (− 2 to − 13%). Warming temperature was identified as the dominant driver for the glacier area changes (r = − 0.85*) and total runoff (r = − 0.75*) at 0.05 level of significance. Our findings indicate a rainfall-runoff-dominant hydrological regime in future, highlighting critical freshwater availability conditions and associated socioeconomic risks in terms of agricultural applications and natural disasters. We recommend building infrastructure for water storage and conveyance in the Indus basin to prevent the adverse impacts of future climate change. © 2022, The Author(s), under exclusive licence to Springer Nature B.V.