Background: Piper guineense (PG) and Sesamum indicum (SI) have been shown to be rich sources of antioxidants and other health benefits; hence, we evaluated the impact of its consumption in hypercholesterolemic model on lipid metabolism. Methods: Forty-eight animals were divided into eight groups of six rats each. Rats were given cholesterol (40 mg/0.3ml), PG and SI extract (100 and 200 mg/kg), and Questran (0.26 g/kg) orally, five times a week for 28 days. Lipid profile, hepatic antioxidant status, biomarkers of liver toxicity, and tissue histopathology were examined. Data were analyzed using one-way ANOVA and P<0.05 were considered statistically significant.Results: Cholesterol feeding caused 100% gain in weight, significantly increased AST, LPO (P=0.41 and 0.002) but significantly decreased SOD (P=0.003) compared to control. CHPG(1)/(2) and CHSI(1)/(2) caused a significant decrease (P=0.01, 0.005, 0.003, and 0.023) in cholesterol-induced body-weight gain and decreased serum total cholesterol by 20-30% compared to untreated-hypercholesterolemic rats. Triglyceride and LDL-c decreased with extract administration and specifically HDL-c increased significantly (P<0.001) by CHSI(1) compared to untreated-hypercholesterol rats. Furthermore, an increase in HDL-c was higher (P=0.04 and 0.002) by SI compared to PG at both doses. Conclusion: These results indicate that PG and SI exerts a hypolipidemic effect, reduces cholesterol intake induced body weight gain, and increases the body’s antioxidant defense system in experimental hypercholesterolemia.