Background: Hepatocellular carcinoma (HCC) is a major health problem, classified among the higheast five most widespread malignancies. Objectives: this experimental study aims to assess the anti-tumor activity of phloretin in treatment of induced HCC in rats. Methods: fifty adult male albino rats were classified into 5 groups (n=10, each). Group I (control group), Group II (DMSO group). Group III (preventive) (pre-treated with phloretin for 14 day before HCC induction and continued during induction period) .Group IV was HCC – Induced (DENA) group. Group V (therapeutic group) (treated with phloretin after HCC induction peroid). At the end of the experiment blood serum samples and liver tissues were collected. Results: the results showed that DENA caused liver damage as proved by significant high increase in (ALT), (AST), (ALP) (GGT) activities and marked significant decrease in albumin content. Also, induced oxidative stress as pointed out an increase in (MDA) and (NO) level and decrease in (GSH), (GST) and (CAT) activity compared with the control values. Also, it decreased apoptotic pathway by decrease in Caspase-3 and Caspase-8 concentration. Treatment with phloretin significantly reduced the elevation in liver enzymes and oxidative stress; it also induced apoptosis by significant increase in Caspase-3 and Caspase-8 concentration compared to HCC group. Conclusions: this study suggests that phloretin plays an important role in protection against DENA induced HCC.