Highlights What are the main findings? Groundwater in the Shule River Basin declined persistently from 2003 to 2023 at -0.31 cm yr-1, with the most severe losses in the central and lower reaches. Natural variability explained most of the early depletion, but human activities became the dominant driver after 2016, closely linked to cropland expansion, urban growth and GDP. What is the implication of the main finding? The intensifying role of human activities highlights the urgent need for adaptive water management in arid inland basins. The integrative framework combining GRACE, land surface models, and socio-economic data offers transferable insights for groundwater sustainability in other water-stressed regions.Highlights What are the main findings? Groundwater in the Shule River Basin declined persistently from 2003 to 2023 at -0.31 cm yr-1, with the most severe losses in the central and lower reaches. Natural variability explained most of the early depletion, but human activities became the dominant driver after 2016, closely linked to cropland expansion, urban growth and GDP. What is the implication of the main finding? The intensifying role of human activities highlights the urgent need for adaptive water management in arid inland basins. The integrative framework combining GRACE, land surface models, and socio-economic data offers transferable insights for groundwater sustainability in other water-stressed regions.Abstract Groundwater is a vital resource in arid regions, where it sustains agriculture, industry, and livelihoods. In northwestern China's Shule River Basin, located in the Hexi Corridor, increasing water stress has raised concerns about the sustainability of groundwater use. However, the relative contributions of climate variability and human activities to groundwater depletion in this region remain poorly quantified. This study investigates long-term groundwater storage changes in the Shule River Basin from 2003 to 2023 using GRACE satellite data combined with GLDAS land surface models. A water balance approach was applied to isolate natural (climatic) and anthropogenic contributions to groundwater storage anomalies (GWSAs). In addition, land use transitions and socioeconomic indicators were incorporated to assess the impact of human development on subsurface water dynamics. The results show a persistent downward trend in GWSA, with an average annual loss rate of -0.31 cmyr-1. Spatially, the central and lower reaches of the basin exhibit the most significant depletion, driven by intensive irrigation and urban growth. Contribution analysis indicates that natural factors accounted for 61% of the groundwater loss across the study period, while anthropogenic drivers became increasingly dominant over time, particularly after 2016, accounting for over 40% of total depletion in recent years. Strong correlations were found between groundwater decline and the expansion of cropland, impervious surfaces, and GDP. These findings highlight the intensifying role of human activities in shaping groundwater trends in arid inland basins. This study provides a data-driven framework to support sustainable groundwater management and offers transferable insights for similar water-stressed regions globally.