The world's largest aquifers are a fundamental source of freshwater used for agricultural irrigation and to meet human water needs. Therefore, their stored volume of groundwater is linked with water security, which becomes more relevant during periods of drought. This work focuses on understanding large‐scale groundwater changes, where we introduce an approach to evaluate groundwater sustainability at a global scale. We employ a groundwater drought index to assess performance metrics (reliability, resilience, vulnerability, and a combined sustainability index) for the largest and most productive global aquifers. Spatiotemporal changes in total water storage are derived from remote sensing observations of gravity anomalies, from which the groundwater drought index is inferred. The results reveal a complex relationship between the indicators, while considering monthly variability in groundwater storage. Combining the drought and sustainability indexes, as presented in this work, constitutes a measure for quantifying groundwater sustainability. This framework integrates changes in groundwater resources due to human influences and climate changes, thus opening a path to assess progress toward sustainable use and water security.