Due to the increasing importance of low-concentrated pollution of water resources, the photocatalytic decomposition of ibuprofen down to low ppm concentrations over zinc oxide catalyst has been studied. The aim of this work was to evaluate the degradation of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen (IBP) using heterogeneous ZnO photocatalyst under UV-C irradiation. The photo catalyst was characterized by field emission scanning electron microscope (FE-SEM) and x-ray diffraction (XRD). The photocatalytic activity of ZnO nanoparticle was evaluated in a cylindrical glass reactor under VU-C irradiation light. Central composite design (CCD) and response surface methodology (RSM) were employed for modeling and optimizing the IBP degradation under different variables such as initial pH, ZnO loading, humic acid concentration, initial IBP concentration, and reaction time. The results of our experiments showed that the reaction time had its highest positive effect on IBP degradation. The correlation coefficient (R2) value of 0.856 indicated a good agreement between the experimental results and the model predictions. Optimization results showed that the maximum IBP degradation was attained at optimum conditions of pH 6.7, catalyst loading 583 mg/L, initial IBP concentration 1.5 mg/L, humic acid concentration 54 mg/L, and reaction time of 95 min. Under these conditions we achieved maximum IBP removal efficiency of 82.97%. In conclusion, ZnO was found to be an effective photo catalyst and a promising alternative for producing free OH radicals for degradation of ibuprofen as an emerging pollutant in water resources.