BACKGROUND: The effect of the methanolic whole fruit extract from Lagenaria breviflora on vital organs and antioxidant enzymes was investigated in this study. MATERIALS AND METHODS: L. breviflora (250, 500 and 1000 mg/kg/b.w.t./day/rat) was fed orally with the cannula to male albino rats for 28 days. At the end of the treatment, the rats were sacrificed and the effect of the extract on histology of the liver, heart, lipid peroxidation, tissue and serum antioxidant enzymes (superoxide dismutase, catalase, glutathione-s-transferase, glutathione peroxidase) activities, glutathione, myocardial marker enzymes (creatine kinase [CK], lactate dehydrogenase [LDH], alanine transaminase [ALT], and aspartate transaminase [AST]) in serum, and heart homogenate were assessed. RESULTS: The extract demonstrated mild organ doses dependent (500 and 1000 mg/kg) pathological alterations in the architectural section of the liver and heart. At 250 mg/kg/b.w.t., the extract caused a significant (P < 0.05) increase in the level of thiobarbituric reacting acids substance and antioxidant enzyme activities, but causes (P < 0.05) decrease in serum and tissue antioxidant capacity at 500 and 1000 mg/kg/b.w.t., respectively. Also on these two doses, a significant (P < 0.05) increase in serum activity of CK, LDH, ALT, and AST and concomitantly decrease (P < 0.05) in heart homogenate were also observed. CONCLUSION: The results suggested that the Fruit of L. breviflora may contain phytotoxic Substances(s) which may be hepatotoxic, cardiotoxic or able to induce oxidative stress at high concentration. Hence, the consumption of the plant should be taken with caution. SUMMARY: Methanolic whole fruit extract from Lagenaria breviflora demonstrate dose dependent mild toxicity on vital organs (Heart and liver) and anti-oxidant enzymes. The fruit of Lagenaria breviflora may contain Phyto-toxic substance (s) which may be hepatotoxic, Cardio-toxic or able to induce oxidative stress at high concentration. Hence, the consumption of the plant should be taken with caution.