Central composite design and response surface methodology (RSM) were implemented to optimize the operational parameters for a cross-flow aerobic sludge reactor (CFASR) in remedying mixed printing and dyeing wastewater (MPDW). The individual and interactive effects of three variables, hydraulic retention time (HRT), pH and sludge loading rate (SLR), on chemical oxygen demand (COD) and terephthalic acid (TA) removal rates were evaluated. For HRT of 15.3–19.8 hours, pH of 7.2–8.1 and SLR of 0.4–0.6 kg chemical oxygen demand (COD) per kg mixed liquor suspended solids per day, COD and TA removal rates of the CFASR exceeded 85% and 90%, respectively. The check experiment revealed that the effluent from the optimized CFASR was stable below the limitation of 100 mg COD/L and the TA concentration decreased by 6.0% compared to the usual CFASR. The results verified that the RSM was useful for optimizing the operation parameters of the CFASR in remedying MPDW.