Background: Being the main metabolic organ, liver stays in touch with toxicity of introduced materials including, drugs. Protection is priceless to avoid complication of liver toxicity. Objectives: This research aimed to assess the protective impact of silymarin (SIL) on hepatotoxicity based on acute paracetamol (APAP) intoxication in rats in comparison with N-acetylcysteine (NAC). Methods: To do so serum was collected and the liver was analyzed for histological findings on rat model-paracetamol toxicity whether alone or in combination with SIL or NAC. The scenario was based on either preconditioning with SIL/NAC before induction of toxicity or afterwards. Serum liver function tests, pro-oxidant/antioxidant status, and proinflammatory markers were detected alongside liver histological study. Results: The results showed that liver function indices, oxidative state, and pro-inflammatory parameters were significantly changed, and histopathological alterations were detected in the liver of the intoxicated group. These modifications were inverted in groups treated with either SIL or NAC. The results of the current study suggested that SIL might be employed as a hepatoprotective drug against liver damage induced by APAP because of its ability to reduce lipid peroxidation, improve antioxidant defense status, and have anti-inflammatory effects. Conclusion: These results are equivalent to NAC therapy which is a standard drug against APAPrelated hepatotoxicity.