Seleno-compounds have picked up significant consideration due to their efficiency as chemotherapeutic agents. The aim of the current work was to elucidate the impact of “Ebselen" on Diethylnitrosamine-initiated hepatocarcinogenesis in male albino rats. Hepatocellular carcinoma was initiated with oral supplementation of diethylnitrosamine (DEN] (15mg⁄ kg body-weight) for 2 months. Ebselen (5mg⁄ kg body-weight) was given orally to rats for 2 months after DEN-administration. Biochemical analysis includes assessment of liver functions (ALT&AST activities), kidney functions (urea and creatinine), determination of reduced glutathione (GSH) and malondialdehyde (MDA) contents in liver tissues [oxidative stress markers], alfa-fetoprotein (AFP) (tumor marker), besides Bcl2 expression and caspase-3 activities (apoptotic markers). The level of some essential trace elements (iron, zinc, copper, calcium and manganese) was also measured. The results revealed the powerful capacity of ebselen in minimizing the changes induced by DEN verified by significant increment in the level of hepatic antioxidant GSH accompanied by a marked decline in MDA concentration (marker of lipid peroxidation). Also, ebselen-treatment decreases ALT & AST activities, urea and creatinine concentrations. The increase of AFP, Bcl2 and the decrease of caspase-3 were less marked. The increase of Fe, Ca and Cu, the decrease of Zn and Mn were improved, compared to DEN-group. Histopathological examinations of hepatocyte cells were in accordance with the biochemical results confirming the potential role of ebselen in minimizing DNE-induced damage. Ebselen-treatment improved the harmful impacts initiated by DEN as it is an effective antioxidant and scavenger of free toxic radicals.