Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation. The chemopreventive effect of silymarin on inflammatory markers and oxidative damage, caspase-3 and antioxidant status as well as the histopathological alterations in hepatic tissue in N-nitrosodiethylamine (DEN)-induced hepatic carcinogenesis in male albino rats was investigated. To induce hepato cellular carcinoma, rats were given DEN injections (i.p, 200 mg/kg b.wt.) three times at a 15 days interval. Seventy five rats divided into five equal groups. Group Ι :( Control group): received no drugs. Group Π :( DEN group). Group III :( DEN + silymarin protected group): orally received silymarin (37.8mg/kg b. wt/day) one week before DEN injection and continued to be 13 weeks. Group IV :( DEN + silymarin treated group): Injected with DEN then orally treated with silymarin from the 8th week till the end of the experiment (13th week). Group V: (normal –silymarin group): received silymarin. Blood samples and liver tissues were collected from all experimental groups at the end of experiment on 13th week. The obtained results showed that, DEN-induced hepatic carcinogenesis significantly decreased super oxide dismutase (SOD) and Catalase (CAT) activities in liver tissue. On the other hand, a marked increase in liver tissue L-Malondialdhyde (L-MDA), DNA fragmentation percent, caspase-3 and nuclear factor -kappa beta (NF-κB) and in serum AFP, IL-6 and TNF-α levels were observed in DEN injected rats. silymarin was able to mitigate liver tissue damage induced by DEN through increasing of SOD and CAT activities in addition to decreasing DNA fragmentation percent, L-MDA, caspase-3 and NF-κB and nuclear factor kappa B P65. These data suggest that silymarin exhibited significant protection against DEN-induced hepatocarcinogenesis, which might be related with the enhancement of the antioxidant activity and the induction of apoptosis