Ca Mau Peninsula (CMP), the southernmost region of the Mekong Delta, is facing a severe loss of land and freshwater. Particularly, the groundwater resources in the complex multilayered aquifer system of CMP are subject to salinization processes, which are not yet fully understood. In this study, an existing groundwater flow model for the CMP was enhanced to a density-dependent transient transport model using the FEFLOW software package, which is based on the finite element method. The study focuses on simulating groundwater salinity in order to better understand the dynamics of groundwater salinization and potential saltwater intrusion pathways in the study area. Time series of Total Dissolved Solids (TDS) concentrations at observation wells were used to compare simulated and observed salinity data in different aquifers. The model allows a multi-factorial evaluation of the spatial groundwater salinity and could also confirm significant inter-annual variability, particularly in the case of shallow aquifers due to the influence of tides and seasonal rainy/dry seasons. Using sensitivity analysis, leakage from upper saline aquifers into lower freshwater aquifers through natural hydrogeological windows and poorly sealed boreholes was identified as a potential major cause for groundwater salinization occurring in the region. The results obtained can serve as an important basis for developing decision-making tools to promote the sustainable use of water resources on the CMP in the future.