This study assessed the surface water quality in Can Tho city, Vietnam, using a combination of water quality, pollution indices, and multivariate statistical methods. Surface water samples were collected at 38 locations with a frequency of 4 times in 2020 (March, June, September, and December) and at the time of high and low tides to analyze for 18 indicators. Results showed that surface water in Can Tho city was contaminated with organic matters and microorganisms. Parameters of pH, turbidity, total suspended solids (TSS), biochemical oxygen demand (BOD), chemical oxygen demand (COD), N-NH4+, and N-NO3- are significantly increased with low tide. Comprehensive pollution index indicated mild to moderately polluted water in March, June, and September and moderately to severely polluted water in December. Organic pollution index revealed that surface water quality in all locations was polluted with organic matters during the study period especially in March and December. The water quality index also indicated that water quality in December was mostly classified as moderate and bad. The principal component analysis indicated that surface water quality could be affected by five main sources that explain 64.40% of the total variation. This significantly caused the fluctuation of pH, temperature, turbidity, TSS, DO, BOD, COD, N-NH4+, P-PO43-, Fe, and As, which should all be the focus for future monitoring. Surface water management in Can Tho city should also emphasize on the wastewater from urbanization and agriculture, which has been recognized by the analysis to have highest contribution to organic, nutrient, and microbial pollutants in the water bodies.