Background: Alcohol-associated liver disease is a major cause of chronic liver morbidity and is primarily mediated through oxidative stress, inflammation, and depletion of endogenous antioxidant defenses. Nigella sativa has been traditionally used for various liver disorders and is reported to possess antioxidant and hepatoprotective properties. This study was done to assess the hepatoprotective and antioxidant potential of Nigella sativa seed extract (NSE) alone and in combination with silymarin in ethanol-induced alcoholic liver injury in rats. Materials and Methods: Hepatotoxicity was induced by chronic oral administration of alcohol in male Wistar rats 30% v/v ethanol (2 ml/100 g body weight) for eight weeks. The animals were divided into six groups: normal control, ethanol control, silymarin (100 mg/kg), NSE 500 mg/kg, NSE 800 mg/kg, and NSE (500 mg/kg) plus silymarin. Serum liver enzymes (AST, ALT, ALP), hepatic lipid peroxidation (MDA), and antioxidant enzymes (SOD, GSH, CAT) were estimated. Histopathological analysis was performed from the hepatic tissue at the end of the study. Data were analyzed using one-way ANOVA and post-hoc multiple comparison test. Results: Ethanol treatment resulted in a significant increase in serum AST, ALT, and ALP levels and raised hepatic malondialdehyde levels along with significant depletion of antioxidant enzymes (p < 0.001). Nigella sativa treatment resulted in a dose-dependent decrease in liver enzymes and lipid peroxidation and in restoration of antioxidant defenses. Nigella sativa and silymarin as a combination was optimal in hepatoprotection, with near normalization of biochemical and antioxidant parameters. Conclusion: Nigella sativa seed extract demonstrates dose-dependent hepatoprotective and antioxidant activity against ethanol-induced liver damage. Combination therapy with silymarin provides increased protection and might be a potentially selective multi-targeted therapeutic strategy for alcoholic liver diseas.