Background: Hepatocellular carcinoma (HCC) remains one of the most prevalent malignancies worldwide, is a leading cause of cancer- related mortality. Andrographolide (ANDRO) and Resveratrol (RSV) are naturally derived polyphenols that showed promising chemo-preventive effects against HCC. Aim: This study aims to elucidate the antitumor, antioxidants, anti-inflammatory and anti-apoptotic effects of Andrographolide or Resveratrol single or in combination in induced hepatocellular carcinoma in rats. Materials & Methods: Swiss male adult albino rats were divided into 6 groups: Group I served as negative control; Group II served as DMSO control ; Group III (HCC group); rats were injected with a single dose of Diethylnitrosamine (200mg/kg.bw) for 5 weeks, Group IV (Andrographolide treated group) rats treated orally with Andrographolide (25 mg/kg.bw) daily for 10 days; Group V (Resveratrol treated group) rats treated orally with resveratrol (2.5 mg/kg.bw) daily for 10 days; Group VI rats treated with combination of Andrographolide and Resveratrol. Blood and tissues samples were collected for some biochemical. Results: DEN induced HCC that characterized by alterations in liver functions, enhanced the levels of antioxidant in liver tissue, and induced oxidative stress and inflammation. Our data showed that Andrographolide and Resveratrol could ameliorate liver injury (alanine transferase, aspartate transferase, and Galectin 3), up-regulate antioxidant systems (decreasing Malondialdehyde, Nitric oxide and increasing superoxide dismutase, glutathione reduced, glutathione –S-Transferase), and reduce IL-6 level. Conclusions: Both natural products have high antioxidant and anti-tumor activities against DEN-induced HCC in rats when used alone, while combination blocked to their effects, so we recommended used it in a single state