Insulin growth factor (IGF) family and their receptors play a great role in tumors’ development. In addition, IGF-1 enhances cancer progression through regulating cell proliferation, angiogenesis, immune modulation and metastasis. Moreover, nicotinamide is association with protection against cancer. Therefore, we conducted this research to examine the therapeutic effects of nicotinamide against hepatocellular carcinoma (HCC) both in vivo and in vitro through affecting IGF-1 and the balance between PKB and Nrf2. HCC was induced in rats by 200 mg/kg, ip thioacetamide. The rat survival, number and size of tumors and serum α-fetoprotein (AFP) were measured. The gene and protein levels of IGF-1, Nrf2, PKB and JNK-MAPK were assessed in rat livers. In addition, HepG2 cells, human HCC cell lines, were treated with different concentrations of nicotinamide. We found that nicotinamide enhanced the rats’ survival and reduced the number and size of hepatic tumors as well as it reduced serum AFP and HepG2 cells survival. Nicotinamide ameliorated HCC-induced reduction in the expression of Nrf2. Moreover, nicotinamide blocked HCC-induced elevation in IGF-1, PKB and JNK-MAPK. In conclusion, nicotinamide produced cytotoxic effects against HCC both in vivo and in vitro. The cytotoxic activity can be explained by inhibition of HCC-induced increased in the expression of IGF-1 and leads to disturbances in the balance between the cell death signal by PKB and MAPK; and the cell survival signal by Nrf2, directing it towards cell survival signals in normal liver cells providing more protection for body against tumor.