The Upper Indus Basin (UIB) is the source of water for millions of people in Pakistan and the world’s largest irrigation system, but its hydro-climatic regime is poorly known. Moreover, the recent acceleration in climate change (CC) leads to serious concerns about current and future water availability and management. This study assessed the hydro-climatic regime, including precipitation, snow-and glacier melt, and water availability for two sub-basins of UIB under current and future climates. The Distance Distribution Dynamics (DDD) model was used to simulate the different components of the hydro-climatic regime, driven by elevation-distributed precipitation from global gridded products. Results revealed that most precipitation in the study area falls in the winter and spring, and river flow depends more on snow-and glacier melt than rainfall. The future projection showed increasing temperature and precipitation and thus increasing flow. The future glacier melt simulations suggest increasing melt contributions, especially from the higher elevations. The findings of this study may assist policymakers and other stakeholders with respect to hydropower and reservoir development, sustained agriculture production, CC adaptation, and efficient water resources management. Future work is recommended to acquire more observational data, field-based investigations and future glacier recessions.