The purpose of the present study was to evaluate the effects of cordycepin (CA) on N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinomas (HCC) and explore its potential mechanisms. Mice were randomly assigned to four groups: control group, NDEA group, NDEA+CA (20mg/kg) group, NDEA+CA (40mg/kg) group. The animal of each group were given NDEA (100ppm) in drinking water. One hour later, CA, which was dissolved in PBS, were intragastrically administered for continuous seven days. The results showed that CA reduced the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in liver and serum. CA also reduced the levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), methane dicarboxylic aldehyde (MDA), and stored the activity of superoxygen dehydrogenises (SOD) in serum. CA could obviously attenuate the hepatic pathological alteration. Furthermore, CA effectively inhibited the phosphorylations of phosphatidylinositol 3 kinase(PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR). In conclusion, our research suggested that CA exhibited protective effects on NDEA-induced hepatocellular carcinomas via the PI3K/Akt/mTOR pathway.