Groundwater aquifers around the world are experiencing stress due to the composite influence of climate change and excessive groundwater withdrawal. Despite this influence, there is still insufficient knowledge on climate-groundwater interaction dynamics in complex aquifers like Australia's Great Artesian Basin. This understanding can inform improved management, which can in turn, increase resilience of groundwater system to on-going groundwater withdrawal and climate change. The main aim of this research was to assess the impacts of climatic change on groundwater storage (GWS) changes over the Great Artesian Basin (GAB) using a range of multi-scale indicators, including Gravity Recovery and Climate Experiment (GRACE)-derived groundwater observations and standardized precipitation evapotranspiration indices (SPEI). Rotated principal component analysis (rPCA) was used to identify climatic hotspots (where GWS variation is particularly sensitive or vulnerable to the impacts of climate change), and correlation analyses were used to assess the relationship between these hotspots and changes in groundwater over space and time. The localized spatial pattern via rPCA was uncovered in the GAB's southeastern region, where annual variations in GWS exhibited conspicuous peaks in 2002, 2014, and 2015. Another finding was that the southeast region of the GAB experienced higher GWS variations as compared to other sub-basins during 2007–2008, which resulted in low groundwater recharge. These findings underscore the variations in GWS within the GAB, emphasizing its responsiveness to climatic variations (e.g., rainfall contributes to recharge of groundwater system and drought intensifies water extraction and restricts discharge). Moreover, this study found a substantial negative correlation (r = −0.7), between SPEI at 12-month scale and GWS variation in the southern GAB region. This relationship highlights the vulnerability of groundwater storage in the southern GAB region to prolonged drought conditions. Furthermore, this study identified positive correlations (r = 0.4 to 0.8), between key climate indices such as the El Niño-Southern Oscillation (ENSO), Pacific Decadal Oscillation (PDO) with GWS anomalies in the southeast and northern GAB regions. These correlations underscore the pivotal roles played by ENSO and PDO in shaping GWS variations in these areas, highlighting the need to incorporate an understanding of these climatic processes into water resource management strategies. This consideration is crucial for ensuring sustainable water management practices that can adapt to the influence of these climate phenomena. These findings provide essential insights into the dynamics of groundwater in the face of changing environmental conditions, with implications for sustainable water management.