The purpose of this study was to evaluate the protective and anti-inflammatory effect of lycopene against (HgCl2) - induced hepato-renal injury and in rats. 30 rats were divided into 3 equal groups. (G1): rats administered distilled water. (G2): rats received 1/20th of LD50 of Hgcl2 orally (2 mg/kg b. w.t/day) over a period of 4 weeks. (G3): rats received (2 mg/kg b. w.t) Hgcl2+ lycopene at a dose of (20 mg/kg b. w.t/orally) for 4 weeks . Obtained results showed increase in serum ALT, AST and ALP activities, urea and creatinine concentrations and liver tissue MDA level in HgCl2 exposed rats. However, a significant decrease in liver tissue GSH concentration with down-regulation in hemoxygenase 1 (HO-1) gene expression and the anti-apoptotic protein Bcl-2 gene in kidney tissue were observed in (G2) Moreover, the qPCR results of kidney tissue revealed up-regulation of mRNA gene expressions levels of TNF-α, NF-kβ , Bax and p53 in (G2) when compared with control group. Administration of lycopene with HgCl2 (G2) caused improvement of all parameters towards its normal ranges. Various histopathological alterations were detected in kidneys and liver of rats treated with HgCl2. Interestingly, rats treated with lycopene +HgCl2 showed marked reduction in these pathological alterations in comparison to HgCl2 (G2). These results suggested that, the potential ameliorating role of lycopene as potent cytoprotective, anti-inflammatory and anti-apoptotic effects against HgCl2 induced hepato renal damage by inhibiting TNF-α mediated activation of the NF-κβ, Bax, and p53 signaling pathways and activation of (HO-1 and Bcl-2 )genes.