The study was conducted to spatiotemporally analyze the quality, location and critical water variables influencing water quality using water monitoring data from the Department of Environment and Natural Resources, Dong Thap province in 2019. The water quality parameters including turbidity, pH, temperature, dissolved oxygen (DO), total suspended solids (TSS), biological oxygen demand (BOD), chemical oxygen demand (COD), nitrite (N-NO₂⁻), nitrate (N-NO₃⁻), ammonium (N-NH₄⁺), total nitrogen (TN), orthophosphate (P-PO₄³⁻), chloride (Cl⁻), oil and grease, sulfate (SO₄²⁻), coliforms, and Escherichia coli (E. coli) were collected at 58 locations with the frequency of four times per year (February, May, August, and November). These parameters were compared with national technical regulation on surface water quality—QCVN 08-MT: 2015/BTNMT. Water quality index (WQI) was calculated and spatially presented by geographical information system (GIS) tool. Pearson correlation analysis, cluster analysis (CA), and principal component analysis (PCA) were used to evaluate the correlation among water quality parameters, group and reduce the sampling sites, and identify key parameters and potential water pollution sources. The results showed that TSS, BOD, COD, N-NH₄⁺, P-PO₄³⁻, coliforms, and E. coli were the significant concerns impairing the water quality. Water quality was assessed from poor to medium levels by WQI analysis. CA suggested that the current monitoring locations could be reduced from 58 sites to 43 sites which can be saved the total monitoring budget up to 25.85%. PCA showed that temperature, pH, TSS, DO, BOD, COD, N-NH₄⁺, N-NO₂⁻, TN, P-PO₄³⁻, coliforms, and E. coli were the key water parameters influencing water quality in Dong Thap province’s canals and rivers; thus, these parameters should be monitored annually. The water pollution sources were possibly hydrological conditions, water runoff, riverbank erosion, domestic and urban activities, and industrial and agricultural discharges. Significantly, the municipal and agricultural wastes could be decisive factors to the change of surface water quality in the study area. Further studies need to focus on identifying sources of water pollution for implementing appropriate water management strategies.