Objective: Pisonia aculeata, is traditionally used in treatment of liver disorder and thought to have a protective effect which may be beneficial to reduce symptoms of hepatotoxicity. The current study evaluated the scientific merit of these anecdotal claims in an in vivo model.Method: Male Wistar rats were administered 250 or 500 mg/kg of Pisonia aculeata extract for 21 days and simultaneously administered paracetamol 750 mg/kg every 72 h by daily oral gavage. At the end of all experimental methods, all the animals were sacrificed by cervical decapitation. Blood samples were collected. Serum was separated and analyzed for various biochemical parameters.Results: The plant extract showed a remarkable hepatoprotective and antioxidant activity against paracetamol induced hepatotoxicity as judged from the serum marker enzymes and antioxidant levels in liver tissues. Paracetamol induced a significant rise in aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin, gamma glutamate transpeptidase (GGTP), lipid peroxides (LPO) with a reduction of total protein, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione S-transferase (GST).Conclusion: Treatment of rats with different doses of plant extract significantly altered serum marker enzymes and antioxidant levels to near normal. The efficacy of the extract at dose of 300 mg/kg was comparable to the standard drug silymarin (50 mg/kg, p.o.). Data indicates a positive effect. More research is required to derive an optimal therapeutic dose.