Raptinal is a novel antineoplastic agent that induces an expeditious intrinsic apoptotic pathway, in addition to the shutdown of mitochondrial function for cancerous cells, because of silver nanoparticles (AgNPs) that have been shown to provide a worthy approach to overcome tumors. In this study, Both Raptinal and Raptinal-loaded silver nanoparticles (AgNPs) were tested as the first time in hepatocellular carcinoma-induced mice to evaluate its efficacy and targeting to HCC. Seventy-two albino male mice of comparable age were classified into six groups; early stage of HCC was induced using diethyl nitrosamine (DEN)/carbon tetrachloride (CCL4). Liver function was assessed in all groups using ALT, AST, total bilirubin, and alpha-fetoprotein (AFP) as well as histopathological examination. Quantitative gene expression of key apoptotic gene markers p53, cytochrome c, and caspase 3 was assessed in all liver homogenates. The results showed that Raptinal-loaded AgNPs group had significant increase in both apoptotic genes of cytochrome c and Caspase 3 at P = 0.0001 compared with Raptinal-free drug group. AFP levels were significantly decreased in Raptinal-loaded AgNPs group compared with both Raptinal-free drug and HCC groups at P = 0.0001. Degenerative changes in the hepatocytes with focal necrosis and inflammatory cell infiltration in histopathology confirm the biochemical analysis. Our study is considered one of the first studies using Raptinal in vivo. Moreover, it showed that Raptinal and/or the combination between Raptinal and AgNPs showed a promising therapeutic agent in treating early HCC.