Description: In the current study, we investigated the protective effects of the caffeine (Caff) on hepatic damage induced by diethylnitrosamine (DEN) administration in rats. Animals were divided into four groups with 10 animals in each group. Animals in group 1 were untreated (control). Rats in group 2 were injected with a single dose of 200 mg/kg DEN, intraperitoneally (DEN group), those from group 3 were intraperitoneally injected with 100 mg/kg caffeine daily for four weeks (Caff group) and rats from group 4 (DEN+Caff) received the same DEN dose as group 2 and daily caffeine treatments as group 3. After 4 weeks, blood was collected for analysis of activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP. Liver specimens were taken for histopathological examination. The single intraperitoneal administration of 200 mg/kg DEN to rats resulted in significantly elevated levels of serum AST, ALT and ALP indicative of hepatocellular damage. Histopathological examination revealed proliferation of stellate cells, necrosis, cell swelling and karyomegaly in DEN and DEN+Caff groups, with lower intensity in the DEN+Caff group. The results from the present study suggested that caffeine exhibited hepatoprotective properties against diethylnitrosamine-induced hepatocellular damage in rats