Silver nanoparticles (AgNPs) have various applications such as their use in the medical field. As they have been reported to show antimicrobial and anti-tumor effects. The main purpose of the current study was to explore the anti-cancer effects of AgNPs administration alone or in a combination with cisplatin (CP) against hepatocellular carcinoma (HCC) in rats. Seventy-five rats (Sprague Dawley albino rats) were used in the present study. Rats were assigned to 5 groups. Group 1 served as normal control. Group 2 was injected intraperitoneally (IP) with a single dose (200 ml/kg) of diethylnitrosamine (DEN), then one week later carbon tetrachloride (CCl4) was injected IP (0.2 ml/kg) two times weekly for 14 successive weeks for the induction of HCC. Group 3 was treated with AgNPs (4 mg/kg) daily. Group 4 was treated with CP (6 mg/kg) once a week. Group 5 was treated with a combination of AgNPs (4 mg/kg/daily) and CP (2.5 mg/kg/weekly). Groups 3, 4, and 5 were treated for 3 successive weeks after induction of HCC. Hematological, biochemical, antioxidant activities, proinflammatory cytokines, and apoptotic genes were evaluated in the current study. Hematological results denoted normocytic normochromic anemia in all examined groups except group 2 which showed macrocytic hypochromic anemia, with thrombocytopenia and leukocytosis in all groups. Significant hypoproteinemia, hypoalbuminemia, and hypoglobulinemia were detected in all groups, with no significant changes (P < 0.05) in globulin in group 5. Significantly decreases in GSH and SOD were recorded in all groups. While the serum AST, ALT activities, and levels of total bilirubin, urea, creatinine, IL-6, TNF-α, AFP, VEGF, BAX, and caspase-3 were markedly elevated. The results revealed a remarkable improvement in group 5 than groups 3, and 4. The obtained results were supported by immunohistochemical and histopathological investigations of the liver tissue.