Intense climate change and intensified human activities have profoundly altered river hydrological processes, exerting significant impacts on the health and security of fluvial aquatic ecosystems. Following the research paradigm of “spatiotemporal evolution?driving mechanism?causal pathways”, this study systematically analyzes the spatiotemporal variation characteristics and driving mechanisms of hydrological regime indices at 18 hydrological stations across the Nan?Beipan River Basin. The Bayesian Estimation of Abrupt change, Seasonality and Trend (BEAST) method is employed to identify non?stationarity and abrupt changes in runoff series, while the Indicators of Hydrologic Alteration?Range of Variability Approach (IHA?RVA) is used to quantify the degree of hydrological regime alteration before and after dam construction. Combined with Extreme Gradient Boosting?SHapley Additive exPlanations (XGBoost?SHAP), Optimal Multivariate Stratified Geodetector (OMGD) and Partial Least Squares?Structural Equation Modeling (PLS?SEM), this study further distinguishes single?factor, multi?factor effects and impact pathways of natural factors and human activities across the whole basin, regulated basins and natural basins. The results show that: (1) Abrupt runoff changes are highly consistent with regional drought and flood events; (2) Reservoir dams induce hydrological regime shifts characterized by decreased high?flow magnitudes and increased low?flow magnitudes, with dam?induced impacts gradually weakening with increasing distance; (3) XGBoost?SHAP results reveal that climatic factors dominate hydrological regime variations in different basins, whereas both OMGD and PLS?SEM indicate that coupled interactions between climate and river network/landscape/human activities are the primary controlling factors for the whole basin, regulated basins and natural basins respectively. Topography, lithology, soil and other factors only affect partial hydrological regime indices. Overall, hydrological regime indices in the karst Nan?Beipan River Basin exhibit nonlinear responses to climatic and underlying surface factors. Regulated basins are mainly governed by the “climate?landscape” coupling mode, while natural basins are dominated by the “climate?human activity” coupling mode. Both modes demonstrate high sensitivity to climate change. Enhanced human disturbances may increase vulnerability risks in natural basins, highlighting the urgent need to monitor and regulate anthropogenic impacts. Future basin water resource management should prioritize extreme hydrological events triggered by climate change, and pay close attention to potential ecological impacts of reservoir regulation and land?use changes (human activities).