Spirulina was shown to exert anti-inflammatory, antioxidant, hepatoprotective properties, and anticancer activity. This study was done to investigate the protective effects of spirullina on DEN induced hepatocarcinogensis in rats. Fourty-five male albino rats were divided into three groups. Group Ӏ :(normal control group): rats administered distilled water only. Group II: rats received diethylnitrosoamine (200 mg/kg b.wt/i.p), 2 weeks later rats received (2 ml/kg b.wt) Carbon tetrachloride (CCl4) orally at 1:1 dilution in corn oil as a promoter of carcinogenic effect. DEN and CCl4 injections were repeated once again after 1 month from first DEN injection. Group III: rats received DEN then treated with spirullina platensis at a dose level of (800 mg/kg b.wt/orally) dissolved in distilled water for 6 weeks. DEN induced HCC showed significant increase in hepatic marker enzymes (ALT and ALP), total bilirubin and alpha fetoprotein (AFP) with marked decrease in serum albumin concentration. Also, the results of molecular analysis in liver tissue revealed significant up-regulation in TNF-α gene expression level. Conversely, down-regulation in tumor suppressor gene p53 and Cyp2E1 gene expression compared with control group. Treatment with spirullina platensis to DEN induced HCC protects the liver cells from damage by regulating the biochemical parameters. Spirullina platensis was able to mitigate liver tissue damage induced by DEN through increasing of Cyp2E1 and P53 in addition to decreasing TNF-α gene expression level and ameliorate all serum liver function parameters. The obtained results suggest spirullina platensis can inhibit the proliferation of HCC cells through inducing tumor cell apoptosis via activation of the p53 pathway, improvement of detoxification Enzyme and suppression of inflammation by inhibition of TNF-α overexpression. Spirullina may thus be used as a potentially promising agent to inhibit HCC cell proliferation and may be a novel natural product for the management of HCC.