A rational water quality assessment program directly affects a success of a national socio-economic development strategy. This study was aimed to evaluate and classify surface water quality in Dong Thap province, Vietnam, using set pair analysis (SPA) and national water quality index (WQI_VN) methods. The water quality data was collected at 58 locations in 2019 by the Department of Natural Resources and Environment of Dong Thap province. Sixteen variables including temperature (°C), pH, turbidity (NTU), dissolved oxygen (DO, mg/L), biological oxygen demand (BOD, mg/L), chemical oxygen demand (COD, mg/L), total suspended solids (TSS, mg/L), ammonia (N-NH₄⁺, mg/L), nitrite (N-NO₂⁻), nitrate (N-NO₃⁻, mg/L), total nitrogen (TN, mg/L), orthophosphate (P-PO₄³⁻, mg/L), chloride (Cl⁻, mg/L), sulfate (SO₄²⁻, mg/L), coliform (MPN/100 mL), and Escherichia coli (MPN/100 mL) were monitored four times a year (58 water samples × 16 parameters × 4 monitoring times). The findings presented that TSS, BOD, COD, N-NH₄⁺, N-NO₂⁻, P-PO₄³⁻, coliform, and E. coli were the main constraints on water quality. The results of the entropy weight calculation indicated that deteriorated water quality was in the order of microbiological > nutrients > organic matters. Surface water quality was evaluated at medium (level III) and poor (level IV) by SPA and WQI_VN, respectively; however, the combination of SPA and entropy weight was considered more efficient in this classification and a positive spatial autocorrelation was also found through Moran’s I. The spatial distribution of water quality based on SPA classification revealed that better water quality was found in the inner parts of the study area. Due to its ease and effectiveness, set pair analysis should be considered for inclusion in the water quality assessment program of Vietnam.