Karst groundwater is the most important source of water supply for Shanxi province, northern China. In this study, different hydrogeochemical indices along with multiple isotope (2H, 18O, and 87Sr/86Sr) were used to identify the main factors controlling groundwater salinization and hydrogeochemical processes in the Xin’an karst groundwater system at Shanxi. The region’s karst groundwater system was divided into three geologically distinct subsystems, namely, the Changzhi–Xiangyuan subsystem (C–X), Huguan–Pingshun subsystem (H–P), and Licheng subsystem (LC). HCO3–Ca·Mg was dominant chemical type for karst groundwater system. The H–P and LC subsystems experienced similar hydrogeochemical processes; from the recharge zone to discharge zone, the Sr2+ content, Sr2+/Ca2+ ratio, and TDS concentrations of karst groundwater gradually increase along the flow direction. However, for C–X subsystem, from the deep buried zone to discharge zone, the Sr2+ content, Sr2+/Ca2+ ratio, and TDS concentrations gradually decrease due to the mixing of fresh water. The main source of karst groundwater was meteoric water, and it is also recharged by surface water and shallow groundwater. The water–rock interactions in conjunction with the cation exchange absolutely predominated in hydrogeochemical evolution of karst groundwater. Major ions, such as Ca2+, Mg2+, HCO3−, and SO42−, originated from the dissolution of carbonate and sulfate minerals. Dissolution of sulfate minerals was the major process for the increase of groundwater salinity. The NO3−, Cl−, and K+ could be attributed to agricultural and human activities, and the Na+ originated from intense mining activities in the study area. The results will facilitate understanding of hydrogeochemical processes and groundwater pollution to enable effective management and utilization of karst groundwater resources.