Objective: This study aimed to develop an auric-lowering peptide of skipjack byproducts (SPBp) with Xanthine oxidase (XOD) inhibition activity and improve the utilization rate of byproducts of skipjack. Methods: Based on the response surface methodology, several parameters affecting this process were investigated, including protease types and enzymatic dosages, pH, temperature, time and their interactions on the content of amino-nitrogen, solid content and XOD inhibition activity. Results: The results showed that trypsin was the best protease. The optimal process parameters were as follows: the dosage of the enzyme was 4%, pH 8.0, temperature 55 ℃, time 5 h, solid-liquid ratio 1∶3 （g/mL）. Under the control of the optimal conditions, the solid content was 4.12%; XOD inhibition activity was 43.941%, which were all in good agreement with the predicted values. SPBp-XOIP showed strong radical scavenging activity against hydroxyl and DPPH radicals with ED50 values of 6.0 mg/mL and 10.0 mg/mL, respectively. Conclusion: The meat of Skipjack has the potential to prepare XOD inhibitory peptides, which can be used as dietary function factors in antioxidant stress and prevention of hyperuricemia.