The South Aral Sea has been massively affected by the implementation of a mega-irrigation project in the region, but ground-based observations have monitored the Sea poorly. This study is a comprehensive analysis of the mass balance of the South Aral Sea and its basin, using multiple instruments from ground and space. We estimate lake volume, evaporation from the lake, and the Amu Darya streamflow into the lake using strengths offered by various remote-sensing data. We also diagnose the attribution behind the shrinking of the lake and its possible future fate. Terrestrial water storage (TWS) variations observed by the Gravity Recovery and Climate Experiment (GRACE) mission from the Aral Sea region can approximate water level of the East Aral Sea with good accuracy (1.8% normalized root mean square error (RMSE), and 0.9 correlation) against altimetry observations. Evaporation from the lake is back-calculated by integrating altimetry-based lake volume, in situ streamflow, and Global Precipitation Climatology Project (GPCP) precipitation. Different evapotranspiration (ET) products (Global Land Data Assimilation System (GLDAS), the Water Gap Hydrological Model (WGHM)), and Moderate-Resolution Imaging Spectroradiometer (MODIS) Global Evapotranspiration Project (MOD16) significantly underestimate the evaporation from the lake. However, another MODIS based Priestley-Taylor Jet Propulsion Laboratory (PT-JPL) ET estimate shows remarkably high consistency (0.76 correlation) with our estimate (based on the water-budget equation). Further, streamflow is approximated by integrating lake volume variation, PT-JPL ET, and GPCP datasets. In another approach, the deseasonalized GRACE signal from the Amu Darya basin was also found to approximate streamflow and predict extreme flow into the lake by one or two months. They can be used for water resource management in the Amu Darya delta. The spatiotemporal pattern in the Amu Darya basin shows that terrestrial water storage (TWS) in the central region (predominantly in the primary irrigation belt other than delta) has increased. This increase can be attributed to enhanced infiltration, as ET and vegetation index (i.e., normalized difference vegetation index (NDVI)) from the area has decreased. The additional infiltration might be an indication of worsening of the canal structures and leakage in the area. The study shows how altimetry, optical images, gravimetric and other ancillary observations can collectively help to study the desiccating Aral Sea and its basin. A similar method can be used to explore other desiccating lakes.