In many coastal regions, groundwater is the sole freshwater resource for drinking and irrigation. However, coastal aquifers often face saline intrusion due to excessive groundwater extraction, climate change, and sea-level rise. This study integrated approaches in geochemistry, geophysics, statistical analysis, and geographic information system (GIS) to identify groundwater salinization pathways in the Ca Mau Peninsula of the Mekong Delta for sustainable protection of the invaluable freshwater resources. We collected 31 well logging data and groundwater samples from 388 wells in the area. A geochemical analysis demonstrated significant salinization in 9% of investigated wells. Calculated entropy-weighted water quality index (EQWI) indicates that only <3% of samples have excellent water quality and about 35% of medium-to-poor water quality groundwater. High salinity is the leading cause of impaired water quality. We combined geochemical and geophysical methods to validate an approach relating well-logging data (formation resistivity) to salinity to determine high-resolution vertical salinity profiles across the aquifer systems. We demonstrated the occurrence of saline groundwater in the surficial aquifers (Holocene and upper Pleistocene) that overlay above fresh and ancient groundwater aquifers (upper middle and lower Pleistocene, and Pliocene). This fresh groundwater is mostly fossil (age >10,000 years) and cannot be recharged directly from rainfall in the area while being highly susceptible to salinization by the downward movement of saline waters from overlaying aquifers. These findings call for appropriate strategies and directives in groundwater management to protect and sustain the critical water resources in the Mekong Delta.