We investigated the stress-induced changes in the lipid and hormonal concentrations in plasma, including cytochrome P450 (CYP)-derived oxidative stress in the liver, and the anti-stress effect of Korean Red Ginseng (KRG) water extract in mice. Stress induction using restraint increased the levels of corticosterone (CORT), glucose, total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) while decreasing in the levels of insulin and high-density lipoprotein-cholesterol (HDL-C), compared with those of unstressed mice. Restraint-stress also increased the generation of reactive oxygen species (ROS) in plasma by 5.4-fold. Moreover, the stress resulted in a 2.8-fold higher production of C-reactive protein (CRP) than the control group. In addition, the catalytic activities of CYP1A2 and CYP3A4 in the liver microsomes were stimulated by 5.5- and 3.8-fold, respectively, and concomitant ROS formation was elevated by 4.3-fold in the liver extract, compared to the normal group. In contrast, the KRG treatment (5, 20, or 50 mg/kg/day) to stress-exposed 3 groups alleviated the increased CORT, TC, LDL-C, ROS, and CRP levels and restored the decreased insulin concentrations. The enhanced each ROS in the plasma and liver, and the CYP enzyme activities were also attenuated in KRG-treated mice in a concentration-dependent manner. In conclusion, these results suggest that KRG ameliorates stress-induced detrimental effects on the plasma and liver of treated mice.