The Mekong Delta, an important agricultural and economic hub in Vietnam, has suffered from severe water quality issues caused by both natural and anthropogenic forces. This paper aims to conduct a rational statistical approach to evaluate the current situation of surface water quality in the Mekong Delta, applying Factor Analysis (FA), Principal Component Analysis (PCA), and Agglomerative Hierarchical Clustering (AHC) to a database of 3117 samples collected by national and provincial monitoring stations. The results revealed significant contamination with organic pollutants (BOD5: 3.50–172.870 mg/L, COD: 6.493–472.984 mg/L), pesticides (e.g., DDTs: n.d to 1.227 mg/L), trace metals (As: 0.006–0.046 mg/L, Cr: n.d–1.960 mg/L), and microbial indicators (Coliforms: n.d–45,100 MPN/100 mL), often higher than the WHO drinking water threshold. PCA/AHC analysis identified the following five major pollution components: (1) organic pollution and sewage/industrial and deposited chemicals (PCA1—23.08% variance); (2) pesticide and agricultural runoff derived contamination with Hg (PCA2—15.44%); (3) microbial pollution of the water was found to correlate positively with Zn and Cu content (PCA3—8.90%); (4) salinity was found to mobilize As and Cr (PCA4—8.00%); (5) nutrient/microbial pollution presumably from agricultural and sewage inputs (PCA5—7.22%). AHC showed some spatial variability that grouped samples in urban/industrial (Cluster 1), rural/agricultural (Cluster 2), and a highly contaminated one, where water was toxic and presented with microbial and Cd contamination (Cluster 3). Levels of pesticides, Cr, and microbial pollution were higher than reported in previous Mekong Delta studies and exceeded regional trends. These results emphasize the importance of holistic water management strategies, including better wastewater treatment, pesticide control, sustainable farming, and climate-adaptive measures to reduce saltwater intrusion and safeguard drinking water quality for the Mekong Delta.

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