The water resources of the Upper Indus Basin (UIB) of Pakistan, are highly sensitive and vulnerable to climate change that can severely impact the food security and livelihood of millions living downstream. So it has become pertinent to understand the hydrometeorological behavior and assess future water resources and its variability under climate change scenarios. This study was designed to analyze the hydrometeorological trends and assess the changes in the contrasting hydrological regime of snow and glacier-fed river catchments of Hunza and Astore River basins of UIB under Intergovernmental Panel on Climate Change (IPCC) climate change scenarios. In this study, fully distributed TOPKAPI model has been used that incorporates the glaciers component and generates all hydrological cycle parameters at very high spatial and temporal scale. MODIS snow cover product (years 2001 to 2015) and field-based hydrological (19662012) and meteorological data (1999-2012) was used to investigate the trend and magnitude of hydrometeorological variables using nonparametric Mann–Kendall and Sen’s Slope methods. The TOPKAPI model was successfully calibrated and validated over five years 1999-2003 with a Nash coefficient ranging from 0.93-0.94. The representative concentration pathways (RCP) 4.5 and 8.5 scenarios of the IPCC were used to project the future trend of hydro-meteorological variables. The Astore River discharge and precipitation trend were significantly (p ≤ 0.05) increased with a Sen’s slope value of 1.039 m3·s−1·yr−1 and 0.192 mm·yr−1, respectively, while the temperature was non-significantly (p ≥ 0.05) increased with the Sen’s slope value of 0.041 °C·yr−1. On the other hand, the Hunza River discharge and temperature significantly (p ≤ 0.05) decreased with a Sen’s slope value of −2.541 m3·s−1·yr−1 and −0.034 °C·yr−1, respectively, while precipitation showed a non-significant (p ≥ 0.05) increasing trend with a Sen’s slope value of 0.023 mm·yr−1. The snow cover in Western Himalayas (Astore River basin) and Central Karakoram region (Hunza River basin) of the UIB had a stable and slightly increasing trend with a Sen’s slope of 0.07%.yr−1 and 0.394%.yr−1, respectively. Under RCP 4.5 and 8.5, the increasing trend in mean temperature was observed in study area with a value of 0.03 °C.yr1 and 0.12 °C.yr-1, respectively. Overall the increasing trend in annual discharge of Astore River and decreasing trend of snow cover was observed under RCPs. Whereas the Hunza River basin followed the same snow cover and discharge trend under RCP 8.5 while under RCP 4.5 the snow cover is decreasing with an increasing trend of the Hunza River discharge till 2070, and then decline in discharge was observed during far future scenario. Based on the results of this study, it can be concluded that since both sub-basins are influenced by different climatological systems (monsoon and westerly), therefore results of those studies where UIB is treated as one unit in hydrometeorological modeling should be used with caution. Furthermore, this study can help to resolve the Karakoram anomaly and potentially be utilized to develop water policy and planning new water harvesting and storage structures, to reduce the risk of flooding.