To investigate the protective effects and the possible mechanisms of (Garlic and zinc oxide (ZnO) coated by cetyl trimethyl ammonium bromide) nanoparticles against N-nitrosodiethylamine DEN induced hepatocarcinoma in rats. Wistar rats were orally administered Garlic nanoparticles 30 mg/kg b.wt, one time per day for 4 weeks and subsequently rats were orally administered DEN with a dose of 20 mg/kg b.wt., five times a week for 6 weeks. The changes of histology, the biochemical indices of serum, and the levels of Caspase 3and DNA fragmentation percent of liver were examined to assess the protective effects. At the end of the study (10 weeks), DEN induced elevation of the serum biochemical indices alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gammaglutamyl transferase, Alpha feto-protein and total bilirubin, and decrease total protein, albumin and A/G ratio. Garlic nanoparticles administration significantly inhibited the increase of the ALT, AST, ALP, GGT, AFP and total bilirubin and increase total protein, albumin and A/G ratio, improved hepatocellular architecture and dramatically inhibited. The mechanistic studies demonstrated that Garlic nanoparticles counteracted DEN induced protein levels of Caspase 3and DNA fragmentation percent were significantly increased. These data suggest that Garlic nanoparticles exhibited significant protection against DEN induced hepatocarcinogenesis, which might be related with the induction of apoptosis.