The study was conducted to analyze surface water quality fluctuations in the the southern region of Vietnam using monitoring data at 58 locations. Seventeen water quality indicators were analyzed including pH, temperature, electrical conductivity (EC), dissolved oxygen (DO), total dissolved solids (TDS), total suspended solids (TSS), chemical oxygen demand (COD), biological oxygen demand (BOD), ammoniacal nitrogen (NH4+- N), nitrite nitrogen (NO2−-N), nitrate nitrogen, iron (Fe), lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), and chloride (Cl− ions). The study used water quality index (WQI), cluster analysis (CA), principal component analysis (PCA), and Entropy weighted methods to analyze surface water quality. The results showed that the surface water was contaminated with organics (low DO and high TSS, BOD, COD), nutrients (high NH4+-N) and Fe. While Pb at some locations exceeded the allowable limit of the national technical regulation, other indicators (Cd, Hg and As) were within this standard. Moreover, DO, TSS, BOD, COD, NH4+-N, Fe, EC, TDS, and Cl− were seasonally fluctuated. WQI classified water quality from bad to very good (WQI = 42–100) due to the impact of hydrological conditions, navigation, wastewater from industrial zones, and fishing ports. The results of CA suggested that it is possible to reduce the 11 sampling locations (from 33 to 22 locations) in clusters 1–6 and the frequency of monitoring from 8 to 5 times per year, which still ensures representativeness of water quality over time. This reduction allows lowering the monitoring costs by 56.5%. The PCA identified five major potential sources explaining 87.3% and 8 minor sources explaining only 12.7% of water quality variation. Temperature, pH, EC, DO, BOD, COD, NH4+-N, NO2−-N, Fe, Cl−, Pb are important indicators need to periodically be monitored. Furthermore, orthophosphate, total phosphate, total nitrogen, coliforms should be considered to add into the next monitoring program. Locations with medium and bad water quality are concentrated in Dong Nai, Ho Chi Minh City and Long An, which requires finding effective solutions to improve the water quality. The current results can assist in decision-making related to environmental quality monitoring in the southern region of Vietnam.