The present work investigated the feasibility of photo-oxidation process for the removal of oil and chemical oxygen demand (COD) in Indian tannery wastewater with the support of mathematical modeling and statistical approach. The influence of process variables such as nano-catalyst dose and reaction time was analyzed on the removal of oil/grease and COD. The obtained results are discussed using the response surface methodology (RSM) design in detail. Zinc oxide nanoparticles prepared from Eclipta prostrata plant leaves and characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), and transmission electron microscopy (TEM). COD removal of 93.6% and oil and grease removal of 90% in 35 min using 3 mg/L nanoparticle dosage were recommended as an optimum condition in photo-oxidation process. PRACTITIONER POINTS: The structure and surface morphology of zinc oxide nanoparticles in spherical shape was confirmed by the SEM with EDX and XRD analysis. Response surface methodology (RSM) with Box-Behnken design (BBD) combination was explained the effect of different parameters on COD and oil and grease removal. The treatment of photo-oxidation process showed chemical oxygen demand (COD) removal of 93.6% and coil and grease removal of 90% in 35 min using mg/L nanoparticle dosage. The obtained result showed that photo oxidation of green synthesized zinc oxide nanocatalyst was found to be an effective method for tannery wastewater.