Xanthine oxidase (XO) produces reactive oxygen species (ROS) and has been associated with vascular endothelial dysfunction. While the effects of xanthine oxidoreductase (XOR) inhibitors on inhibiting the generation of uric acid from xanthine have been reported, much less is known about their effects on XO-induced ROS. The mechanisms of action of each XOR inhibitor vary, but it is not known whether XOR inhibitors’ effects on oxidative stress also vary. The purpose of this study is to compare the effects of different XOR inhibitors on XO-induced ROS. We used an in vitro chemiluminescence assay with clinically relevant doses of XOR inhibitors (allopurinol, oxypurinol, febuxostat, and topiroxostat) to investigate their effects on circulating XO-derived ROS. All XOR inhibitors significantly inhibited ROS production, with febuxostat and topiroxostat showing strong effects. These results confirm differences in the effects at clinical did among XOR inhibitors on XO, with topiroxostat demonstrating a strong suppression of ROS production. This study should help guide clinical practice in using XOR inhibitors to improve patient care and management.