Protected places such as nature reserves (NRs) are used to maintain ecological balance, biodiversity, and support surrounding ecosystems. However, the development and operation of infrastructure such as dikes and sluice gates in NRs, as seen in the Vietnamese Mekong Delta (VMD), often adversely affects the hydrological regime and water quality at both local and regional scales. This study analyzes the consequences of a constructed dike system on the hydrological regime and water quality in the NRs through an integrated approach including hydrochemical analysis (using descriptive statistics and weighted arithmetic water quality index (WAWQI) analysis), traditional interviews (face to face), using semi-structured questionnaires, field surveys, and secondary data. Results show that constructed infrastructure has helped maintain water supplies for both livelihoods and forest fire prevention. However, considerable impacts on the hydrological regime and water quality have occurred. From water quality assessments in three NRs, 29% of sampling sites in the My Phuoc melaleuca forest (MPMF) had WAWQI values over 100, while all sites in Lung Ngoc Hoang NR (LNHNR) and Mua Xuan Agriculture Center (MXAC) had WAWQI values over 100. This was to a large extent due to elevated concentration of chemical oxygen demand (COD), biological oxygen demand (BOD5), and phosphate (PO43−). Meanwhile, during the wet season, pollution was marginally reduced by dilution, with 42.86% of sites at Lung Ngoc Hoang NR, 28.57% of sites at MXAC, and 78.57% of sites at MPMF having WAWQI values of less than 100. These results show the issue of water pollution at spatio-temporal scales, and call for better holistic management options for improving the hydrological regime and water quality.