The study focused on the effect of methanol leaf extract of Simarouba glauca (MESG) on lipoproteins cholesterols and oxidative stress biomarkers in male Wistar rat. Toxicological inquest of MESG was evaluated as prescribed in the guidelines of organization for economic co-operation and development (OECD), No. 425. A total of twenty-four male Wistar rats were used; divided into four groups of six rats each, including the control. Test rats were given MESG 500, 1000 and 2000 mg/kg body weight respectively, daily for thirty (30) days. At the end of the study, the rats were fasted overnight and sacrificed and biochemical indicators were evaluated. Results showed marked increase (p ˂ 0.05) in Total Cholesterol at MESG 2000 mg/kg; a reduction and increase (p ˂ 0.05) in High-Density Lipoprotein Cholesterol and Triglycerides respectively, at all doses; an increase (p ˂ 0.05) in Low- Density Lipoprotein Cholesterol at MESG 2000 mg/kg. Additional data indicated no changes (p ˃ 0.05) in Malondialdehyde levels; liver Catalase was significantly (p ˂ 0.05) expressed at MESG 500 and 2000 mg/kg, kidney CAT was significantly (P ˂ 0.05) expressed at all doses. The liver Superoxide Dismutase (SOD) was significantly (p ˂ 0.05) expressed at MESG 1000 and 2000 mg/kg; the kidney and heart SOD were also significantly (P ˂ 0.05) expressed at MESG 500 and 2000 mg/kg respectively. The plasma GSH-PX was significantly (P ˂ 0.05) expressed at MESG 1000 mg/kg; while the liver and heart GSH-PX were significantly (P ˂ 0.05) expressed and repressed at 500 mg/kg respectively. Conclusively, MESG elicited obvious dyslipidemia; accompanied by marked alterations in selected endogenous oxidative stress biomarkers.