The present study was aimed to investigate the hepatoprotective and antioxidant activities of ethanol extract from Monochoria vaginalis (250 mg/kg and 500 mg/kg B/W) on acetaminophen (APAP) induced rat hepatic injury. Monochoria vaginalis is a traditional medicinal plant that is commonly used to treat and improve liver conditions in India and other Asian countries. The development of hepatotoxicity induced by APAP is promoted by oxidative stress. APAP treated group significantly (P < 0.01) elevated the serum enzymatic levels like glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, alkaline phosphatase (SALP), total bilirubin and malondialdehyde (MDA), which were restored towards normalization significantly (P < 0.01) thanol extract of yonochoria vagin is (EEMV). In addition, the EEMV significantly (P < 0.01) elevated the decreased level of total protein and antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase and reduced glutathione. Apart from these, histopathological changes also showed the protective nature of the EEMV against APAP induced hepatic damage in liver tissues. The activity of EEMV at 500 mg/kg B/W was comparable to the standard drug silymarin (25 mg/kg B/W). In conclusion, these data suggest that the EEMV possess hepatoprotective and antioxidant effects against APAP-induced hepatotoxicity and oxidative stress in rats.