The flower heads of Sphaeranthus indicus Linn (Asteraceae) a traditional Indian medicinal plant is commonly used to nourish and improve the liver conditions. This study was designed to evaluate the hepatoprotective and antioxidant effect of aqueous (AQS) and methanolic (MES) extract of flower heads of Sphaeranthus indicus on Acetaminophen (APAP)-induced heptotoxicity in rat’s in-vivo. Activities of liver marker enzymes ,glutamate-oxaloacetate transaminase (SGOT) glutamate pyruvate transaminase (SGPT), acid phosphatase (ACP) and alkaline phosphatase (ALP) bilirubin and total protein at an oral dose of MES (300mg/kg) showed a significant hepatoprotective effect in comparison with the same dose of aqueous extract. This fact was also confirmed by studying the liver histopathology of treated animals. As Regards the antioxidant activity, MES exhibited a significant effect showing increasing levels of superoxide dismutase (SOD), Catalase (CAT), and glutathione peroxides (GPX) by reducing malondialdehyde (MDA) levels.