Palm oil mill effluent (POME) is a highly polluted agro-industrial wastewater. The CO2 in industrial flue gas requires treatment before it can be discharged into the environment. Utilizing microalgae as the agent to treat wastewater and industrial flue gas is a waste-to-wealth approach. The resulting biomass can be commercialized in the form of valuable products. Chlorella sp. is a microalgal species that can tolerate the pollutant load and has been proven to be a suitable species for CO2 fixation. In this study, Chlorella sp. was cultivated in POME with the aim of reducing the pollutants in the POME and simultaneously capturing CO2. The optimization of the operational conditions of this microalgae-based treatment system was carried out using the response surface methodology (RSM) face centered-central composite design (FC-CCD). Operational factors include the air concentration of CO2 (10-25% v/v), the inlet gas flow rate of 500-2000 mL min−1, and initial inoculum concentration (10-30% v/v) of Chlorella sp. cultivated in POME. The target deliverables include the maximum amount of CO2 fixed by Chlorella sp. and the total nitrogen (TN) reduction as indicators of pollutant reduction by this treatment system. We found that a limited supply of CO2 caused growth limitation, while excess CO2 resulted in acid production that triggered microalgae growth inhibition. The optimum operational conditions were 10% v/v CO2, 1670 mL min−1 aeration rate, and 24.8% v/v inoculum concentration, predicted to simultaneously fix CO2 at 0.12 g of CO2 L−1 day−1 and reduce 80.9% TN, respectively. [ABSTRACT FROM AUTHOR]