This study utilized MIKE 11 to quantify the spatio-temporal dynamics of water quality parameters (Biochemical Oxygen Demand (BOD5), Dissolved Oxygen (DO) and temperature) in the Long Xuyen Quadrangle area of the Vietnamese Mekong Delta. Calibrated for the year of 2019 and validated for the year of 2020, the developed model showed a significant agreement between the observed and simulated values of water quality parameters. Locations near to cage culture areas exhibited higher BOD5 values than sites close to pond/lagoon culture areas due to the effects of numerous point sources of pollution, including upstream wastewater and out-fluxes from residential and tourism activities in the surrounding areas, all of which had a direct impact on the quality of the surface water used for aquaculture. Moreover, as aquacultural effluents have intensified and dispersed over time, water quality in the surrounding water bodies has degraded. The findings suggest that the effective planning, assessment and management of rapidly expanding aquaculture sites should be improved, including more rigorous water quality monitoring, to ensure the long-term sustainable expansion and development of the aquacultural sector in the Long Xuyen Quadrangle in particular, and the Vietnamese Mekong Delta as a whole.