Background Tramadol administration is associated with hepatic congestion, apoptosis and induces oxidative damage in tissues. The thiol group in N-acetyl-cysteine (NAC) interacts directly with reactive oxygen species leading to cellular protection against such damage. Aim The present study was designed to highlight the hazards of tramadol (TR) on liver structure of adult male albino rat and the efficacy of NAC on the histological structure, liver functions for protection against such possible induced hazards. Materials and methods Forty male albino rats were used. Rats were divided into four groups with 10 rats per each group. Control group received normal saline 2ml/day orally by gavage for 30 days. NAC- treated group received 150 mg/kg/day of NAC dissolved in normal saline by oral gavage for 30 days. TRtreated group received TR 40mg/kg/day dissolved in normal saline by oral gavage for 30 days. TR + NAC group were administered TR and NAC in similar doses as in TR and NAC groups' respectively for 30 days. The livers were removed and processed for light microscopic examination and different biochemical markers in addition to immunohistochemical examination of both Bax and 8- hydroxyl-2-deoxy guanosine (8-OHDG). Results The TR- treated group revealed disrupted arrangement of the hepatic cords together with congestion of central vein and mononuclear perivascular infiltration. Most of the hepatocytes showed necrosis and apoptotic hepatocytes with bile duct duplication. There were diffuse fibrous tissue formation and a significant increase in the number of Bax and 8-OHdG positive cells. As regard to liver functions, there were highly significant elevations of serum levels of aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Serum alkaline phosphatase (ALP) and bilirubin and reduction of serum albumin. As regard to the antioxidant enzymes, there was an increase of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in the liver tissues. In contrast with TR+NAC group where liver parenchyma restored its uniform architecture with minimal collagen fibers, significant reductions in the number of Bax and 8-OHdG positive cells. Liver functions and antioxidant enzymes level nearly restored its normal values. Conclusion The TR is suggested to have hepatotoxic effect and NAC might have protective effects against such induced hepatotoxicity.