Objective: The aim of this study was to investigate the effects of Cisplatin and Annona muricata's efficacy, safety, and tolerability in treating liver cancer in rats. Method: Animals: 56 male albino rats, 3–4 months old, weighing 180–200 g on average, were purchased and brought to the animal house at the Department of Biochemistry Faculty of Science, Zagazig University. Rats used in the experiment were split into 4 groups, as follows: 14 healthy rats in Group (1) are left untreated (Negative Control). 42 healthy rats were separated into three equal groups, after receiving an IP dose of CCl4 (1 ml/kg/ twice a week for 8 weeks) to induce HCC. Group (2) consists of 14 rats with liver cancer which were not treated (Positive control). Group (3) has 14 liver cancer-afflicted rats, received IP dose of Cisplatin (6 mg/kg/week for 4 weeks). Group (4) has 14 liver cancer-afflicted rats that were given oral dose of Annona muricata (300 mg/kg every day for 4 weeks). Results: At the end of experiment blood samples were taken from all rats in all groups to preserve the serum for estimation of serum liver enzymes (AST, ALT and ALP), Serum proteins (total protein, albumin, globulin and A/G ratio), serum kidney function tests (urea and creatinine) and inflammatory marker (TNF-α). Liver tissues were collected for gene expression determination of PI3K and Akt levels and histopathological study. Conclusion: The present study indicates that Annona muricata gives significant results in treatment of Albino rats with liver cancer, due to its antioxidant, anti-inflammatory and anticancer effects beside improvements of hepatorenal cellular, so we should interest in research in the same field with conducting experiments using Annona muricata as a protective agent for the liver against cancer.