In this study, spatiotemporal fluctuations in surface water quality in Vinh Long province, Vietnam, were conducted using entropy weighting, water quality index (WQI), and multivariate statistical techniques, such as cluster analysis (CA), principal component analysis (PCA), and discriminant analysis (DA). The samples collected at 63 monitoring locations in March, June, and September were measured for 15 parameters. Compared to the Vietnamese standard, surface water was contaminated with organic matters, nutrients, microorganisms, and salinity. DA identified the most typical parameters (pH, turbidity, TSS, EC, DO, Cl−, E. coli, coliform) in distinguishing temporal variations in water quality with greater than 75% of the correction. CA group 63 sampling sites into 22 clusters representing different land use patterns. WQI determined the worst water quality was found in the agricultural areas. Based on the results of entropy weighting, EC, coliform, N-NH4+, BOD, N-NO3−, and Fe had significantly controlled surface water quality. Four principal components obtained from PCA explained 66.45% of the variance, suggesting the influences of geohydrological factors and anthropogenic activities, such as domestic, market area, agriculture, and industry. The findings of this study can provide useful information for authorities to evaluate the effectiveness of monitoring systems and plan for water quality management strategies.