In this study, the performance of oxidation with actived persulfate (PS) by graphene oxide-TiO2 nanosheet (GO-TiO2) was investigated for diclofenac (DCF) removal, an anti-inflammatory analgesic being widely used in human health care and veterinary treatment. GO-TiO2 containing oxygen functional groups is employed as an activator for the activation of PS used as the oxidizing agent. Modeling and optimization of the process were performed by central composite design (CCD) as a response surface methodology (RSM). The effects of various factors, including PS concentration, GO-TiO2 amount, initial pH of DCF solution, and reaction time on DCF oxidation, were evaluated. When the estimated values of the full quadratic model obtained with CCD were compared with the actual experimental results, a strong agreement was obtained with an R-2 value of 0.9553. Besides, the model consistency was verified by analysis of variance (ANOVA) with a value of 20.17 of F value and P value of less than 0.05. After the optimization run, maximum DCF removal of 93.06% occurred with contact time of 14 min, pH of 5.54, PS concentration of 10 g/L, and 0.1 g of GO-TiO2 as optimal variable values.