Introduction: Hyperlipidemia is a lipid metabolic disorder and the major risk factor for the development of cardiovascular diseases (CVDs). Because most of the current hypolipidemic drugs are expensive with potential side effects, the research focusing on natural alternative medicines is relevant. The fruit extract of Vitex doniana is used by some traditional medicine practitioners in Nigeria to treat CVDs. This study is aimed at investigating the hypolipidemic and antioxidant effects of ethanol fruit extract of V. doniana in high-fat diet (HFD) induced in albino rats. Oral administration of extract at 250, 500 and 1000 mg/kg body weight on HFD induced hyperlipidemia lasted for 28 days. Atorvastatin (1.2 mg/kg) served as standard drug. Hypolipidemic effect was checked by the measurement of serum lipid profile and effect on oxidative stress. Results: The results revealed a dose dependent significant (P<0.05) decrease in malondialdehyde (MDA), increase in superoxide dismutase (SOD) and catalase (CAT) levels when compared to the negative control. This attests to the ability of the extract to boast the antioxidant defence mechanism in the animals. Positive effect on CVDs was further confirmed by the observed dose related significant (p<0.05) reduction in serum lipids (total cholesterol, total glycerides and low density lipoprotein) profile of the treated rats when compared to the negative control. Conclusion: The fruit extract of V. doniana possesses serum lipid lowering effects; its folkloric use in the treatment of cardiovascular diseases could therefore be justified. Further studies need to focus on the isolation and characterization of the secondary metabolites responsible for this observed activity.