Introduction: Alstonia scholaris Linn. is the common ingredients of various herbal formulation. Objectives: Present study was aimed to evaluate the oxidative and histopathological alterations in acetaminophen (APAP) induced hepatotoxicity and protective mechanisms of different leaf extracts of A. scholaris. Methods: Forty two wistar rats were randomly divided into seven groups with six rats in each and subjected to different treatments. Alterations in total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), total thiols (TTH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-s-transferase (GST), malondialdehyde (MDA) levels and histopathological alterations in hepatic tissue were analyzed to assess the extent of hepatic damage induced by APAP and the protection imparted against it by aqueous or ethanolic leaf extract of A. scholaris. Results: Single high oral dose of APAP administration increased (p<0.05) hepatic levels of TOS, OSI and MDA and reduced TAS, TTH, SOD, CAT, GPx and GST activities indicating alteration in antioxidant system of hepatic tissue. The histopathological studies showed severe hepatic degeneration, vacuolization and granulation in cytoplasm, fragmentation of nuclei and membranes and infiltration of mononuclear cells on APAP treatment. Pre and post-treatments of aqueous or ethanolic extract following APAP administration restored TTH, reduced MDA and TOS and increased TAS compared to APAP treatment alone. Conclusions: Observations of histopathological and antioxidant parameters indicates that restoration of TAS and TTH levels by leaf extracts may be the primary protective mechanism in APAP induced hepatotoxicity. Further treatments with ethanolic extract showed more hepatoprotective potential than the aqueous extract of A. scholaris.