Mining cities are ecotone areas where human and natural components interact. Indeed, the negative effects of mining activities on drinking water quality have become a serious public concern worldwide. To elucidate groundwater genesis and reactive transport path controlling the water pollution, a multi-bodies system in the Sunan Mine area in China was considered in this study. The results of the mineral phase characterizations, hydrochemical analysis, and multiple stable isotopes (δ2H/δ18O, δ34S and 87Sr/86Sr) indicated that calcite, dolomite, gypsum, quartz, halite, organic carbon, and gases (O2, CO2 and H2O) were the primary reactants in the aquifer system, accompanied by dissolution and precipitation of minerals, cation exchange, desulfation, and evaporation. An inverse hydrogeochemical model was employed to identify three paths, Path 1 demonstrated that mine water mainly originated from the Quaternary loose aquifer water (QLA), Permian fractured sandstone aquifer water (PFA), and Carbonifer fractured limestone aquifer water (CFA), accompanied by high K++Na+ and HCO3− concentrations due to the carbonate dissolution, halite dissolution, and cation exchange processes. Path 2 showed that the recharge of the CFA and Ordovician fractured limestone aquifer (OFA) occurred from the shallow recharge zone to the deeper OFA water through faults and fractures, mainly involving halite dissolution, carbonate dissolution, and gypsum dissolution. Path 3 demonstrated the interaction between the Hui River, collapsed pond water, and QLA, accompanied by gypsum dissolution, calcite dissolution, and cation exchange. Although the shallow QLA quality met the WHO drinking water standards, the pollution risk from the surface collapse pit water cannot be ignored. Therefore, effective approaches need to be considered in the study area to reduce the connection between the collapse pit water and QLA. The study results can help decision makers to predict water quality of complex water systems in ecotone areas and other similar regions worldwide.