A coagulation-flocculation process was used to treat papermaking-reconstituted tobacco slice wastewater with polyaluminium chloride (PAC) as coagulant and a cationic polyacrylamide (CPAM) as flocculant. To maximize the reduction of chemical oxygen demand (COD) and color, the jar tests were carried out in the experiments and response surface methodology (RSM) was applied to optimize the process. A central composite design, i.e., a standard approach in RSM, was used to evaluate the effects and interactions of three factors, i.e. PAC dosage, CPAM dosage and pH on the treatment efficiency. Results revealed that the maximum reduction of COD and color could be achieved at an optimal conditions, i.e., PAC = 715 mg/L, CPAM = 4.8 mg/L and pH = 6.6, from which the reduction of COD and color were 67.8% and 77.7%, respectively. The study also showed that the regression equations could be used as the theoretical basis for coagulation-flocculation process of papermaking-reconstituted tobacco slice wastewater. They will be very helpful to flexibly select the appropriate process parameters in the engineering applications.