Abstract: Background The ten first-level water resource regions in China exhibit significant variations. In-depth exploration of these differences are critical for optimizing water resource management strategies and solutions. This study aimed to analyze the systematic differences among primary water resource regions under the influence of hydrological, ecological, and meteorological drivers. Methods This study established a multi-dimensional evaluation framework based on hydrology-ecology-water use indicators. Using Pearson correlation analysis and principal component analysis (PCA), we investigated inter-variable mechanisms with datasets by 2021–2023 and the long-term average data. Results We concluded: (1) Pronounced spatial disparities were observed in hydrological characteristics. The precipitation, runoff depth, and vegetation coverage in the southern regions are all greater than those in the northern regions, and the total precipitation in the southern regions shows a generally stable trend. Southern regions demonstrated abundant water resources and balanced water–heat conditions, with runoff volumes 3.51–4.21 times greater and runoff depths 2.76–3.92 times higher than those in northern regions. The Yangtze River Basin contained the most abundant surface water resources, reaching 945.59 billion m³, while the north regions possessed relatively high groundwater resources, amounting to 75.85 billion m³; (2) Regarding water use efficiency indicators, the Northwest Rivers Region ranked highest in both per capita comprehensive water use (2005.33 m³/person) and water use per RMB 10,000 GDP. The Pearl River Basin recorded the highest irrigation water use per mu (671 m³/mu); (3) Hydrological processes are synergistically driven by multiple factors such as climate and water use. Precipitation is positively correlated with vegetation coverage, runoff volume is positively correlated with groundwater resources, and runoff depth shows a significant negative correlation with annual sunshine hours; Conclusion Regional clustering indicated that the Songhuajiang, Liaohe, Haihe, Yellow River, and Huaihe River Basins shared characteristics of water-stressed regions, whereas the Yangtze River, Zhujiang, and Southwest River Basins were relatively water-abundant. Water-stressed regions should accelerate efficient water resource utilization and ecological restoration efforts, in addition to promoting water-saving agriculture. This study reveals synergistic mechanisms underlying regional heterogeneity and provides theoretical support for optimizing water-use efficiency and resource allocation strategies.