Cyclosporine A (CsA) is a strong immunosuppressive drug, but its use is frequently accompanied by severe renal toxicity. The potential renoprotective effect of Thymoquinone (TQ) against CsA-induced nephrotoxicity in rats was assessed. Thirty adult white male albino rats were divided into three equal groups. Group I: (Normal control), received no drugs, Group II: (CsA treated), rats received oral dose of Cyclosporine A (25 mg/kg b.wt/day) for 21 days. Group III: (TQ protected + CsA), received Thymoquinone (10 mg/kg b.wt/day) orally 7 days before and during 21 days of CsA treatment. The obtained results showed a significant increase in the concentration of urea and creatinine in serum and L-MDA level in kidney tissue with marked decrease in renal catalase activity and GSH concentration in CsA treated rats. Moreover, a significant down-regulation in Bcl-2 and up-regulation of NF-κB, PAI-1, Caspase-3 and p53 gene expressions levels were observed in kidney tissues of CsA treated rats. Also, various histopathological alterations were detected in kidneys of CsA treated rats. Meanwhile, TQ potentially improved renal function and oxidative alterations related to CsA near its normal ranges. Interestingly, histopathological findings supported that TQ markedly attenuates harmful effects that CsA induced and protected kidney. Our research could conclude that, TQ has an ameliorating role as potent antioxidant, anti-inflammatory and anti-apoptotic agent via inhibition of inflammatory (NF-κB, PAI-1) and apoptotic (Caspase-3, p53) signaling pathway in modulation of CsA-induced nephrotoxicity.