Harmful algal blooms (HABs) severely disrupt aquatic ecosystems by degrading water quality and producing unpalatable off-flavors in aquaculture products. Copper sulfate pentahydrate (CuSO4·5H2O) has been used for decades as an affordable and FDA-approved algaecide to manage HABs. However, growing concerns about negative environmental impacts and the diminishing efficacy of treatments over time have prompted the exploration of alternative strategies. This project evaluated the synergetic effects of low-dose CuSO4·5H2O treatments following pH manipulation with carbon dioxide (CO2). The addition of CO2 lowers pH, which is hypothesized to increase Cu toxicity to cyanobacteria. To test this, large ~1600 L mesocosms were placed in a eutrophic pond and treated with a low dose (0.33 mg/L CuSO4·5H2O) or a micro dose (0.08 mg/L CuSO4·5H2O), which are 20% and 5% of the standard dosing recommendations, respectively. These were tested alongside untreated controls. Half of each of the treatments also received a CO2 addition that dropped the pH in the enclosures from 9.15 to 7.58 for the first 3 days of the experiment. The addition of CO2 for the micro dose of CuSO4·5H2O resulted in 14% greater removal of cyanobacteria in the first 24 h and 20% more removal of off-flavors in the first 3 d, which was significantly more effective than treatments without CO2. After one week, treatments with CuSO4·5H2O and CO2 additions continued to significantly reduce harmful cyanobacteria (>94%) and off-flavors (>95%); however, beneficial green algae were significantly promoted (+512%) in these treatments, which was not observed in treatments without CO2 or the controls. This approach ultimately mitigated cyanobacteria and off-flavors while preventing the unintended consequences of CuSO4·5H2O treatment, all while using just 5% of the copper dose that is typically recommended. These findings offer crucial insights for water resource managers on how to best optimize CuSO4·5H2O use for effective and sustainable HAB mitigation.