Purpose: To investigate the possible hepatoprotective potential of Parthenium hysterophorus crude extract (Ph.Cr) against carbon tetrachloride (CCL4)- and paracetamol-induced hepatotoxicity in rabbits.Methods: Twenty rabbits were divided into five groups of four rabbits each. Group 1 served as normal control and received normal saline (5 mL/kg). Group 2 received normal saline followed by CCL4 (0.75 mL/kg p.o dose) after 1 h. Groups 3 and 4 received Ph.Cr at doses of 15 and 30 mg/kg po, respectively, for 7 days followed by one dose of CCL4, 2 h after the last extract dose (0.75 mL/kg, sc). Group 5 received silymarin as reference standard at a dose of 100 mg/kg orally for 7 days followed by one dose of CCL4 (0.75 mL/kg, sc), 2 h after the last drug dose. The effect of the extract on potassium (K+)- induced contractions in isolated rabbit jejenum was also evaluated. At the end of the study, the animals were sacrificed and their liver architecture examined microscopically.Results: Pre-treatment of rabbits with Ph.Cr reduced ALT, ALP and TB levels (p < 0.05, p < 0.01, p < 0.001) dose dependently. Hepatoprotective data indicate that Ph.Cr markedly reduced CCL4- and paracetamol-induced toxicity by preserving the histological architecture of the liver tissue at near normal. In isolated rabbit jejunum tissue, Ph.Cr relaxed high K+ (80 Mm)-induced contractions in a concentration-dependent (0.03 - 10 mg/mL) manner like that caused by silymarin.Conclusion: In the light of the results obtained, Parthenium hysterophorous possesses hepatoprotective activity against CCL4- and paracetamol-induced hepatic damage, possibly mediated via its antioxidant and Ca++ antagonist mechanisms.Keywords: Parthenium hysterophorus, Toxins, Hepatoprotection, Ca++ antagonist, Silymarin