In this study, the photocatalytic regeneration by ZnO was employed for the regeneration of the granular activated carbon (GAC) which was saturated with the reactive red 43. The ultrasound was applied as a pretreatment step due to the cleanup of the adsorbent surface and providing a higher surface area and adsorption capacity. According to the nitrogen gas adsorption-desorption results, the ultrasound pretreated-GAC had the highest surface area and the total pore volume. The SEM and XRD analyses confirmed the immobilization of ZnO nanoparticles on the GAC. Response surface methodology (RSM) was used to model and optimize the preparation of the granular activated carbon/ZnO nanocomposite. The sonication time, pH, GAC/ZnO ratio, and calcination temperature were used as four effective parameters on nanocomposite preparation. Optimum amounts of pH, GAC/ZnO ratio, calcination temperature, and sonication time were found to be equal to 4, 5, 300 °C, 210 min, respectively; in these conditions, 83.98% of the capacity of the exhausted granular activated carbon was regenerated. ANOVA results, high R, R-adj values, and also normal and random distribution of residuals showed that application of RSM for the modeling and optimizing the preparation step of GAC/ZnO nanocomposite was successful.