Climate extremes such as droughts and intense rainfall events are expected to strongly influence global/regional water resources in addition to the growing demands for freshwater. This study examines the impacts of precipitation extremes and human water usage on total water storage (TWS) over the Ganges-Brahmaputra-Meghna (GBM) River Basin in South Asia. Monthly TWS changes derived from the Gravity Recovery And Climate Experiment (GRACE) (2002–2014) and soil moisture from three reanalyses (1979–2014) are used to estimate new extreme indices. These indices are applied in conjunction with standardized precipitation indices (SPI) to explore the impacts of precipitation extremes on TWS in the region. The results indicate that although long-term precipitation do not indicate any significant trends over the two subbasins (Ganges and Brahmaputra-Meghna), there is significant decline in rainfall (9.0 ± 4.0 mm/decade) over the Brahmaputra-Meghna River Basin from 1998 to 2014. Both river basins exhibit a rapid decline of TWS from 2002 to 2014 (Ganges: 12.2 ± 3.4 km3/yr and Brahmaputra-Meghna: 9.1 ± 2.7 km3/yr). While the Ganges River Basin has been regaining TWS (5.4 ± 2.2 km3/yr) from 2010 onward, the Brahmaputra-Meghna River Basin exhibits a further decline (13.0 ± 3.2 km3/yr) in TWS from 2011 onward. The impact of human water consumption on TWS appears to be considerably higher in Ganges compared to Brahmaputra-Meghna, where it is mainly concentrated over Bangladesh. The interannual water storage dynamics are found to be strongly associated with meteorological forcing data such as precipitation. In particular, extreme drought conditions, such as those of 2006 and 2009, had profound negative impacts on the TWS, where groundwater resources are already being unsustainably exploited.