The aim of this study was to evaluate the antioxidant mechanisms of red ginseng essential oil (REO) in cells as well as in an animal model. REO was prepared by a supercritical CO2 extraction of waste-products generated after hot water extraction of red ginseng. In HepG2 cells, REO diminished the H2O2-mediated oxidative stress and also restored both the activity and expression of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Administration of REO inhibited the phosphorylation of upstream mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38. In mice, the CCl4-mediated elevation of serum aspartate transaminase and alanine transaminase as well as the induction of hepatic lipid peroxidation were decreased by REO administration. REO treatments also resulted in up-regulation of the antioxidant enzyme expression in the liver. Moreover, increased phosphorylations of MAPKs were inhibited after REO administration. Overall, REO seems to protect the liver from oxidative stress through the activation and induction of antioxidant enzymes via inhibition of MAPKs pathways.