The sonocatalytic Removal of Rifampin by Nitrogen-doped Zinc oxide/Graphene oxide hybrid nanocomposite (N: ZnO/GO) is reported in this study. The structural properties of the nanocomposites were confirmed by the X-ray diffraction (XRD), the scanning electron microscopy (SEM), the transmission electron microscopy (TEM), the X-ray energy spectroscopy (EDX) and the diffraction reflectance spectroscopy (DRS). The experiments were investigated by applying the Response Surface Methodology (RSM) using the Design of Experiments software. Analysis of variance (ANOVA) confirmed that the quadratic model has good reliability for predicting the sonocatalytic efficiency with different operational factors (R 2 = 0.9958 and Adjusted R 2 = 0.9920). According to the RSM data, the optimized nanocomposite (N: ZnO (0.2 M)/GO (0.1 g)) demonstrated a reasonable catalytic activity for sonocatalytic degradation of RIF at the initial concentration (30 mg L À 1 ), the ultrasonic irradiation time (60 min), natural pH and under the ultrasonic irradiation power of 400 W with a reaction rate constant of 0.0466 min À 1 which was higher compared with the other ones. The residual RIF amount has determined by the spectrophotometric method. The percentage of the RIF minerals was 80.8 % after 60 min of RIF degradation over N: ZnO (0.2 M)/GO.[a] Ā.