The objectives of this study were to appraise groundwater quality using entropy-weighted water quality index (EWQI), identify the potential pollution sources using principal component analysis (PCA), and assess human health risks related to groundwater consumption. Thirty-five water samples were collected in the coastal Mekong Delta regions (Ben Tre, Bac Lieu, Soc Trang provinces) and analyzed for eleven parameters. The results revealed that more than 70% of total groundwater samples with concentrations of pH, total dissolved substance, total hardness, nitrate (NO3−), sulfate (SO42−), chloride (Cl−), iron (Fe), manganese (Mn), and arsenic (As) were in the permissible limits. Meanwhile, over 50% of total samples exceeded the limits for ammonium (NH4+) and coliform in groundwater. The computed EWQI values ranged from 8 to 71,700, with most samples classified as “excellent” and “good” quality (accounted for 45.7% and 20%, respectively). The PCA results help identify potential pollution sources, including seawater intrusion, industrial and domestic wastewater, water–rock interaction, and agricultural and aquacultural wastes. Drinking groundwater contaminated Fe, Mn, and As has potentially caused adverse health effects for both adults and children (hazard quotient > 1). The carcinogenic risks of arsenic-contaminated water were up to 1.74×10−4 for males, 1.78×10−4 for females, and 9.12×10−5 for children. These findings can significantly contribute to understanding the susceptible groundwater source in the coastal provinces under the impacts of human and natural activities and associated high human health risks. Therefore, it is necessary to have proper management strategies to protect this freshwater source and effective groundwater treatments to reduce human health risks.