The study employed different statistical approaches to assess surface water quality in the upstream region of the Vietnamese Mekong Delta. The dataset included seven parameters (i.e., temperature, pH, total suspended solids (TSS), five-day biological oxygen demand (BOD5), chemical oxygen demand (COD), ammonium nitrogen (NH4+-N) and coliform) at seventy-three locations. Cluster analysis (CA) and principal component analysis (PCA) were applied to analyze spatial variations in surface water quality and recognize the important parameters. The findings revealed that surface water quality was deteriorated by organic matters (high BOD5 and COD), nutrients and microorganisms. Particularly, urban areas were found to be more polluted than the other areas. The PCA results indicated that three potential water pollution sources, including industry, urban and tourism, could explain 87.03% of the total variance. Coliform was identified as the leading latent factor that controls surface water quality in the study area. CA grouped the sampling locations into 11 groups, in which the groups of the baseline monitoring sites and large rivers had better water quality. The results indicated a significant impact of anthropogenic activities (especially, urban and tourism practices) in surface water quality degradation. Moreover, CA suggested that the numbers of the sampling sites could be reduced from 73 to 58 locations, lowering 20.54% of the monitoring cost. Thus, the study recommends scrutinizing the current surface water quality monitoring system to be more economic and urgently implementing appropriate solutions to mitigate coliform pollution in the smaller water bodies.