Groundwater abstraction and depletion were assessed at a 1-km resolution in the irrigated areas of the Indus Basin using remotely sensed evapotranspiration (ET) and precipitation; a process-based hydrological model and spatial information on canal water supplies. A calibrated Soil and Water Assessment Tool (SWAT) model was used to derive total annual irrigation applied in the irrigated areas of the basin during the year 2007. The SWAT model was parameterized by station corrected precipitation data (R) from the Tropical Rainfall Monitoring Mission, land use, soil type, and outlet locations. The model was calibrated using a new approach based on spatially distributed ET fields derived from different satellite sensors. The calibration results were satisfactory and strong improvements were obtained in the Nash-Sutcliffe criterion (0.52 to 0.93), bias (−17.3% to −0.4%), and the Pearson correlation coefficient (0.78 to 0.93). Satellite information on R and ET was then combined with model results of surface runoff, drainage, and percolation to derive groundwater abstraction and depletion at a nominal resolution of 1 km. It was estimated that in 2007, 68 km3 (262 mm) of groundwater was abstracted in the Indus Basin while 31 km3 (121 mm) was depleted. The mean error was 41 mm/year and 62 mm/year at 50% and 70% probability of exceedance, respectively. Pakistani and Indian Punjab and Haryana were the most vulnerable areas to groundwater depletion and strong measures are required to maintain aquifer sustainability.