Background: Hepatotoxicity induced by Cyclosporine A (CsA) remains one of the major side effects. The aim of this study was to determine the protective effects of beet root (Beta Vulgaris L) extract and silymarin against hepatotoxicity induced by Cyclosporine A in rats. Methods: Sixty male albino rats, were divided into 6 groups (n=10). Group I control group. Group II CsA-treated and received (50mg/kg weight, orally). Group III received (500mg/kg b.wt) beet root extract orally. Group IV received beet root extract and CsA as in group II and III. Group V was received (100 mg/kg b.wt) silymarin orally. Group VI received CsA and silymarin as in group II and V. Serum levels of (ALT, AST, ALP) and bilirubin (Total and Direct) were measured. Oxidative stress biomarkers, antioxidant status, damage to DNA, apoptosis and inflammatory mediators were measured in the tissues of the liver. Result: CsA administration significantly increased serum levels of the liver enzymes ALT, AST, ALP and bilirubin. In addition, significant increase in MDA, Nitrite, 8-OHdG, caspase3, NF-κB, TNF-α and significant decrease of GST in liver tissues was noticed. Furthermore, histopathological changes occurred in CsA treated rats exhibited disruption of normal liver architecture, congested central vein, vacuolated cytoplasm and inflammatory cells infiltration. Co-administration of beet root extract or silymarin +CsA ameliorated all these parameters. Conclusion: The present study suggests that beet root extract and silymarin have beneficial effect in reducing hepatotoxicity induced by CsA via decreasing oxidative stress, inflammation, DNA damage, apoptosis and repairing the histopathological changes.