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Although numerous studies on hydrogeochemistry in karst catchments have been performed, some challenges in understanding their hydrogeochemical behavior remain due to the unique architecture of karst groundwater systems and the high heterogeneity of the karst medium. Here we used a multicriteria approach combining hydrodynamic, hydrochemical, and stable isotopic tools to investigate the impact of heterogeneity on karst hydrogeochemistry in a mountainous area of Hubei Province, Central China. Our results showed that groundwater was dominated by Ca2+, Mg2+, HCO 3 −, and SO 4 2−, and typically characterized by HCO 3 –Ca·Mg type in the shallow aquifer and by SO 4 –Ca·Mg type in the deep aquifer. With increasing circulation depth, water-rock interactions and the heterogeneity of the karst medium produced water with increased Ca2+, Mg2+, Sr2+, and SO 4 2− concentrations, and also increased the dissolved total solids. Calcite, dolomite, and gypsum dissolution in local and intermediate flows were important geochemical processes in groundwater evolution, and calcite precipitation occurred in the regional flow due to dedolomitization, supported by PHREEQC modeling of minerals. The decreased major ions and increased nitrate with increasing δ18O due to the dilution of shallow groundwater by high δ18O recharge and nitrogen fertilizer required during the summer rainy season were found relying on Plots of δ18O vs major ions, which offer an alternative approach to learn seasonal effects of hydrogeochemistry. All advances presented were integrated into a hydrogeochemical conceptual model, including local, intermediate, and regional flows, hydrogeochemical evolution, horizontal and vertical karst zones, hydrochemistry, and stable isotopes of groundwater, providing a typical model for multiple karst groundwater systems in Central China. [Display omitted] • Impact of heterogeneity on karst hydrogeochemistry was studied based on hydrodynamic, hydrochemical, and stable isotopic tools. •Time series analysis and circulation depths of groundwater highlighted the existence of the Sixi multiple karst groundwater systems. •Calcite, dolomite, and gypsum dissolution were important geochemical processes in local and intermediate flows, and dedolomitization occurred in the regional flow. •A hydrogeochemical conceptual model representing multiple karst groundwater systems in Central China was proposed. [ABSTRACT FROM AUTHOR]