The sustainable development of groundwater resources in arid and semi-arid regions is a challenging task hindered by climate change and human activities. The rational utilization and management of groundwater resources is, therefore, dependent on an understanding of the influences of human and climatic factors on the spatial distribution of groundwater resources and their change over time. The thick Quaternary aquifers in the Yinchuan Basin, China were used herein as an example of how to quantitatively assess spatial and temporal trends in groundwater resources in response to human activities and climate change. A 3D transient groundwater flow model was constructed and used to simulate the evolution and spatial variability of hydrogeological processes from 1990 to 2020. By subsequently applying regime shift detection and correlation analysis to the simulation results, we found that: 1) groundwater storage was continuously depleted over the 30-year period, reaching a cumulative depletion of 1.89×10⁹ m³; 2) human activities were mainly responsible for variations in regional hydrogeological processes for a period of up to 30 years. Climate only affected short-term interannual fluctuations in groundwater storage; 3) human activities (e.g., river water diversion and groundwater abstractions) were the decisive factors causing a continuous reduction of groundwater resources. A policy-driven reduction in water diversion from the Yellow River directly led to a significant drop in groundwater storage, which had a consequent effect on surface water and groundwater interactions and altered agricultural irrigation patterns (crop patterns and irrigation methods); 4) the amount of groundwater recharge from the Yellow River and local lakes increased from 1990 to 2020, whereas the discharge of groundwater to the Yellow River and lakes decreased.