The present study was designed to explore the effects of lithium and ethanol in the markers of lipid peroxidation, antioxidant enzymes and reduced glutathione activities on oxidative stress induced by methylphenidate (MPD) and corticosterone (CORT) in the brain tissues. The studies were conducted on the brain of adult male mice for 21 days. The concentrations of MPD 2.0 mg/kg BW and CORT 20.0mg/Kg BW were administered via intraperitoneally. However, LiCl 50.0 mg/kg BW and EtOH 2.0 g/kg BW was dissolved in water and administered via oral gavage. We observed thiobarbituric acid reactive substances (TBARS) levels, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx) enzymes and reduced glutathione (GSH) activities by the spectrophotometer. Our results demonstrated that MPD and CORT treatment triggers oxidative stress in brain as revealed by an increased level of lipid peroxidation, and decreased levels of glutathione peroxidase and reduced glutathione respectively. We also noticed that the SOD and CAT activities were significantly higher in the CORT groups. Histopathological evaluation demonstrated that lithium did not show visible improvement in the MPD and CORT treatment groups. In addition, long-term ethanol treatment increased reactive oxygen species level in the brain. From these results it is possible to conclude that concomitant administration of LiCl with EtOH may enhance the toxicity in the brain tissues. Studies with larger samples are warranted to further clarify this issue.