Azithromycin (AZ) is a broad-spectrum antibiotic however AZ hepatotoxicity limits its therapeutic indications. This study clarifies the hepatotoxicity of AZ on albino rat and the possible protective effect of antioxidants; Nigella sativa (NG), Vit. C (VC) or Silymarin (SL) against AZ hepatoxicity both histopathologically and biochemically. Thirty rats were randomly divided into 5 groups, 6 rats each; Negative control group, AZ group received AZ (200mg/kg/day) orally for 7 days, NG/AZ group received oral NG oil (4ml/kg/day) for 7 days then NG plus AZ for another 7 days, VC/AZ group received oral VC (500 mg/kg/day) for 7 days then VC plus AZ for another 7 days, SL/AZ group received oral SL (200 mg/kg/day) for 7 days then SL plus AZ for another 7 days. The liver specimens of AZ group showed degenerative changes of the hepatic cords. There were dilated central veins with marked portal inflammatory cell infiltration and increase in collagen fibers. Area percentage of Bcl2 immuno-positive cells is significantly decreased while that of Bax is significantly increased. Moreover, AZ group showed significant increase in liver enzymes and oxidative parameters in comparison to control group. Either NG/AZ, VC/AZ or SL/AZ groups showed marked attenuation of liver toxicity both histologically and by normalizing liver enzymes and oxidative parameters. SL/AZ group showed the least hepatic affection. This work concludes that administration of either NG, VC or SL before and with AZ attenuates its hepatotoxicity possibly through their liver cytoprotective and antioxidant effects and this was more obvious with SL administration.