In this study we investigated the hepatoprotective effects and possible mechanism of Acacia catechu in acetaminophen (APAP) induced hepatotoxicity using female Wistar rat model. Hepatotoxicity was induced by oral administration of acetaminophen (750 mg/kg body weight) for 24 h. The seed (400 mg/kg body weight) and bark (400 mg/kg body weight) extract’s treated groups exhibited hepatoprotective effects and was compared with well-known clinical anti-dote N-acetylcysteine (NAC). When groups treated with acetaminophen, significant increase of liver weight/body weight ratio, liver function enzymes such as alanine aminotransferase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) and decrease of antioxidant enzymes such as glutathione (GSH) and superoxide dismutase (SOD) were observed. The histopathology of APAP treated groups also showed moderate degree of sinusoidal congestion, centrilobular necrosis with polymorph nuclear cells infiltration, marked vacuolations and congestion. However, pretreatment with seed or bark extract groups decreased LPO accumulation, reduced the liver function enzymes and increased antioxidant defense enzymes. Moreover, histopathology of seed extract treated groups showed normal architecture whereas bark extract treated groups exhibited mild degree of vacuolations in the hepatocytes with minimal sinusoidal congestion. Taken together, our study concludes that A. catechu seed extract to be a more promising agent for protecting liver from APAP induced hepatotoxicity.