Hepatocellular carcinoma (HCC) is one of the main causes leading to cancer mortality. Luteolin derived from celery and has anti-cancer activity. Cisplatin is used as a chemotherapeutic agent for the treatment of HCC. A major problem with Cisplatin is the development of Cisplatin chemo resistance. This study aims to evaluate the role of Luteolin in HCC treatment and as a chemo-sensitizer for Cisplatin treatment of HCC in rats. Sixty rats were divided in to sex groups, 10 rats each, group 1: normal control group, group 2: cisplatin (1.5 mg/Kg b.wt) for four weeks and group 3: received the Diethyl nitrosamine (DEN) (20 mg/kg b.wt), group 4: received DEN as in group 3 and then treated with cisplatin, group 5: received DEN as in group 3 and then treated with Luteolin (0.2 mg/kg b.wt) and group 6: received DEN as in group 3 and then treated with cisplatin and Luteolin. After 10 weeks animals were sacrificed and liver tissue were removed for Histopathological and tissue parameters examination. A significant increase in serum serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activity, a significant decrease in serum albumin concentration. Also a significant increases in liver transforming growth factor-beta 1 (TGF-b1), B-cell lymphoma 2 (Bcl-2) and nuclear factor kappa β (NF-kβ) concentrations and a significant decrease in Caspase.3 activity were recorded in DEN-treated rats while treatment with Luteolin and Cisplatin reduced the severity of HCC and enhanced histopathological findings, these result suggesting the efficacy of Luteolin supplementation as an anti-HCC.