Selenium (Se) nanoparticle is a novel Se species with a unique biological activity and low toxicity. This experiment was constructed to explore new approach in recession of hepatocellular carcinoma using selenium nanoparticles. Biochemical and immunohistochemical markers were conducted to prove our hypothesis. Seventy adult male albino rats were randomly assigned into seven groups. Negative control, Nano-Se, HCC, HCC + Doxo, HCC + Nano-Se (therapeutic), HCC + Nano- Se (protection), HCC + Doxo + Nano-Se. The biochemical results revealed significant ameliorative effect of Nano-Se administration on liver enzymes (ALT, AST and ALP) in serum. Circulating level of α-fucosidase and α-fetoprotein and carcinoembryonic antigen were significantly depleted upon administration of Nano-Se. Regarding immunohistochemical findings, the expression of β-catenin, survivin and Ki-67 was downregulated as a result of Nano-Se administration prior or post induction of HCC. The present study sheds light on the potent role of Nano-Se in retrogression of hepatocellular carcinoma in the experimental model. This study represented a new modality in the treatment of HCC using the aspect of nanotechnology.