The influence of climate change and anthropogenic activities (e.g., water withdrawals) on groundwater basins has gained attention recently across the globe. However, the understanding of hydrological stores (e.g., groundwater storage) in one of the largest and deepest artesian basins, the Great Artesian Basin (GAB) is limited due to the poor distribution of groundwater monitoring bores. In this study, Gravity Recovery and Climate Experiment (GRACE) satellite and ancillary data from observations and models (soil moisture, rainfall, and evapotranspiration (ET)) were used to assess changes in terrestrial water storage and groundwater storage (GWS) variations across the GAB and its sub-basins (Carpentaria, Surat, Western Eromanga, and Central Eromanga). Results show that there is strong relationship of GWS variation with rainfall (r = 0.9) and ET (r = 0.9 to 1) in the Surat and some parts of the Carpentaria sub-basin in the GAB (2002–2017). Using multi-variate methods, we found that variation in GWS is primarily driven by rainfall in the Carpentaria sub-basin. While changes in rainfall account for much of the observed spatio-temporal distribution of water storage changes in Carpentaria and some parts of the Surat sub-basin (r = 0.90 at 0–2 months lag), the relationship of GWS with rainfall and ET in Central Eromanga sub-basin (r = 0.10–0.30 at more than 12 months lag) suggest the effects of human water extraction in the GAB.