In the current investigation, Annona muricata Linn. lyophilized fruit pulp powder was evaluated for its hepatoprotective activity induced by paracetamol or acetaminophen (APAP). Male Sprague Dawley rats were orally pre-treated for 15 days with A. muricata lyophilized fruit pulp powder at low (1 g/kg b.wt) and high doses (2 g/kg b.wt). Silymarin (100 mg/kg) was administered as the standard drug. Hepatotoxicity was induced using APAP, in a single oral administration of 2.5 g/kg body weight dosage on the 15th day. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were elevated in the APAP group but were found to be significantly reduced in the pre-treated groups in a dose-dependent manner. APAP administration brought down the serum total protein and albumin levels significantly. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase were reduced in the APAP administration; further, the reduced glutathione pool in the tissue was also diminished significantly. However, with the administration of Annona lyophilized fruit pulp powder, the level of antioxidant parameters was near normal. A significant increase in lipid peroxidation was observed in the APAP group, while the silymarin, AML, and AMH groups exhibited resistance to lipid peroxidation (LPO), as evident from lower levels of LPO generated. Histopathological examination also revealed considerable tissue damage in the APAP alone treatment group, which was not devastating in the silymarin, AML, and AMH groups. Altogether, the study concludes that the lyophilized fruit pulp of A. muricata is protective against APAP-induced liver injury in rats by modulating the hepatic redox systems.