Cyclosporine A (CsA) is a drug used as immunosuppressive agent in organ transplant and non-transplant medicine. The main secondary effect results from CsA treatment is nephrotoxicity. A protective effect of Grape seed proanthocyanidin extract (GSPE) against CsA-induced nephrotoxicty in rats was assessed. Thirty male rats were divided into three equal groups. Group I: (Normal control), received no drugs, Group II: (CsA treated), rats received oral dose of CsA (25 mg/kg b.wt/day) for 21 successive days. Group III: (GSPE protected+ CsA), rats received GSPE (200 mg/kg b.wt/day) orally 7 days before and during 21 days of CsA treatment. The obtained results showed a significant increase in serum urea and creatinine concentration in addition to L-MDA levels in kidney tissue while a 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 were observed in kidney tissues of CsA treated rats. Meanwhile, GSPE potentially improved renal function and oxidative alterations related to CsA near its normal ranges. Also, various histopathological alterations were detected in kidneys of CsA treated rats. Interestingly, histopathological findings supported that where GSPE markedly attenuated the harmful effects induced by CsA and protected kidney tissues. Our research could conclude that, GSPE 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.