Groundwater salinization is currently a very serious and challenging issue in many parts of the world. With an increasing demographic pressure and remarkable changes of water and land uses over the last decades, the multilayer coastal aquifer system of Jiangsu province, east China, was affected by increasing salinization. In this study, we investigate the groundwater salinization process and the salinity sources of the aquifer system in Nantong area (southern part of the Jiangsu coastal plain) using a multi-isotope (δ2H, δ18O, 87Sr/86Sr, and δ11B) approach. The results show that the TDS (total dissolved solids) values in most deep groundwater samples are generally lower than those of the shallow groundwater samples. The TDS of both shallow and deep groundwater increase from western Nantong (inland) to the eastern coastal region of the Yellow Sea. The chemical types transform from Ca-Mg-HCO3 or Mg-Ca-HCO3 to NaCl. The stable hydrogen and oxygen isotopes signatures of the groundwater samples indicate that local precipitation likely acts as the main recharge source of both the shallow and deep confined groundwater systems. The deep groundwater shows more depleted isotopes, suggesting recharging by the precipitation under a cold climate before the Holocene period. The shallow groundwater features heavier water isotopes, indicating recharging source from recent precipitation under a warm climate. The variations in δ11B and 87Sr/86Sr of groundwater samples can be explained by the changes of solute sources. In the inland region (western Nantong), shallow groundwater with higher TDS is mainly caused by evaporation-induced concentration, whereas in coastal areas, seawater intrusion exerts a major influence on the chemical composition of the shallow groundwater.Our results show that that seawater intrusion mainly occurs in eastern and southeastern Nantong area. We also find that hydraulic connection between shallow and deep groundwater is strengthened by continuous overexploitation, and deep groundwater is mixed with shallow groundwater at some points. The mixing between upper saline water and deep freshwater, together with water-rock interactions, likely explain the observed low salinity in deep groundwater in coastal areas. Overall, with growing observations of salty seawater intrusion in the estuary region of the Yangtze River, future efforts are needed to prevent further seawater intrusion as sea level rises and groundwater table declines. In this context, our findings provide key information for groundwater management in other coastal aquifers, east China.