Our previous research demonstrated that a novel phenolic glucoside, origanoside, isolated from Origanum vulgare, exhibits significant antimelanogenesis activity. The present study was designed to investigate whether origanoside may serve as a quencher of oxidative insults and is involved in antimelanogenesis. It is found that origanoside exhibit the radical-scavenging capacity of 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS+) and superoxide anion radical (O2−), the reducing power, and the inhibition ability of lipid peroxidation (LP). Pretreatment with origanoside in hydrogen peroxide (H2O2)-treated BNLCL2 and HaCaT cells increased the activities of catalase (CAT) and glutathione peroxidase (GPx), potentially reducing the amount of reactive oxygen species (ROS) generation. These findings confirm the cytoprotective effect of origanoside in hepatocytes and keratinocytes, suggesting that origanoside exhibits antioxidant activities and may be a useful food additive.