Optimization of an integrated anaerobic-aerobic bioreactor (IAAB) treatment system for the reduction of organic matter (Chemical Oxygen Demand (COD), Biochemical Oxygen Demand (BOD) and Total Suspended Solids (TSS) concentrations) in Palm Oil Mill Effluent (POME) to legal standards with high methane yield was performed for the first time under thermophilic condition (50°C–55°C) by using response surface methodology (RSM). The experiments were conducted based on a central composite rotatable design (CCRD) with three independent operating variables, organic loading rates in anaerobic compartment (OLR ) and mixed liquor volatile suspended solids (MLVSS) concentration in anaerobic (MLVSS ) and aerobic compartments (MLVSS ). The optimum conditions for the POME treatment were determined as OLR of 15.6 g COD·L ·d , MLVSS of 43100 mg·L , and MLVSS of 18600 mg·L , where high aerobic COD, BOD and TSS removal efficiencies of 96.3%, 97.9%, and 98.5% were achieved with treated BOD of 56 mg·L and TSS of 28 mg·L meeting the discharge standard. This optimization study successfully achieved a reduction of 42% in the BOD concentrations of the final treated effluent at a 48% higher OLR as compared to the previous works. Besides, thermophilic IAAB system scores better feasibility and higher effectiveness as compared to the optimized mesophilic system. This is due to its higher ability to handle high OLR with higher overall treatment efficiencies (more than 99.6%), methane yield (0.31 L CH ·g COD ) and purity of methane (67.5%). Hence, these advantages ascertain the applicability of thermophilic IAAB in the POME treatment or even in other high-strength wastewaters treatment.