The research investigated changes in surface water quality (SWQ) in the canals and rivers of Can Tho province in the Mekong Delta in southern Vietnam. Surface water was sampled at 34 points through months of the end of the rainy and flood season (October 2023), the beginning of the dried season (December 2023), and the middle of the dried season (February 2024). The SWQ parameters were compared with limited values of the national technical standard on SWQ and the Vietnamese water quality index. We used principal component analysis (PCA) to find sources causing surface water pollution and cluster analysis (CA) to identify the similarities in SWQ parameters among sampling points. The research showed that Can Tho’s average SWQ value ranged at a good level. The SWQ in the dry season is worse than in the rainy season. Pollution from suspended solids, organic matter, nutrients, and coliform was found in Can Tho’s surface water. The PCA resulted in the three key sources of PCs 1, 2, and 3 being elucidated by 65.3% of SWQ changes. Twelve current monitoring parameters, including temperature, pH, dissolved oxygen, total suspended solids, total organic carbon, biological oxygen demand, chemical oxygen demand, ammonium, nitrite, nitrate, phosphate, and coliform, are influencing SWQ. It is suggested from the CA results that the 34 monitoring points could decrease to 30 points in the case of financial issues. The results are beneficial in reviewing the sampling points and monitoring parameters for SWQ in Can Tho.