Factors affecting biogas production from synthetic wastewater in upflow anaerobic sludge blanket (UASB) reactor by anaerobic granular sludge were optimized using Response Surface Methodology (RSM) with Box‐Behnken Design. COD,
NH4+‐N and sulphate were investigated as the experimental parameters. The experiments were conducted in 500 mL serum bottles with a working volume of 300 mL. The optimum conditions were determined as COD of 5610 mg L−1,
NH4+‐N of 100 mg L−1 and sulphate of 1830 mg L−1 according to the experimental design. Under the optimal conditions, a maximum biogas yield of 604.05 mL, COD removal of 95.87%,
NH4+‐N removal of 42.94% and sulphate removal of 80.29% were obtained. COD and sulphate showed the greatest individual and interactive effects on biogas yield (P < 0.05). COD had an individual effect on biogas yield (P < 0.0001) and
NH4+‐N also had an individual effect on COD removal (P < 0.0001). The confirmation experiments conducted under the optimal conditions resulted in a biogas yield of 589.75 mL, COD removal of 94.09%,
NH4+‐N removal of 39.31% and sulphate removal of 74.37%. The differences between predicted values and experimental results were satisfactory. The model had practical directive significance for optimizing key factors affecting biogas production from synthetic wastewater by anaerobic granular sludge. Optimizing COD,
NH4+‐N, and sulphate can improve biogas production. © 2016 American Institute of Chemical Engineers Environ Prog, 36: 11–20, 2017