Cyclosporine A (CsA) is the most widely used immunosuppressant in organ transplant surgery and in treatment of autoimmune disease. Nevertheless, animal and clinical studies have demonstrated that nephrotoxicity is the major adverse effect limiting the prolonged CsA therapeutic use. The present study aimed to investigate possible protective effect of sildenafil, a phoshodiestrase-5 inhibitor, on CsA-induced nephrotoxicity and various mechanism(s) underlies this effect. Male Wistar rats were administered CsA (20 mg/kg/day, s.c.) for 21 days alone or in combination with sildenafil (5 mg/kg/day, p.o.). Sildenafil exhibited nephroprotective effects as evidenced by significant decrease in serum creatinine and urea levels, spot urine albumin–creatinine ratio, as well as levels of renal malondialdehyde and nitric oxide, with a concurrent increase in renal level of reduced glutathione and catalase activity compared to CsA-treated rats. Additionally, immunohistochemical analysis demonstrated that sildenafil treatment markedly reduced inducible nitric oxide synthase, tumor necrosis factor-alpha, and caspase-3 expressions, while expression of endothelial nitric oxide synthase was prominently enhanced. The protective effects of sildenafil were confirmed by renal histopathological examination. Pretreatment with l-nitro-arginine methyl ester (10 mg/kg/day, i.p.), a non-selective nitric oxide synthase inhibitor, reversed the protection afforded by sildenafil. Taken together, the current study highlighted the renoprotective effects of sildenafil against CsA-induced nephrotoxicity in rats, which might be mediated, in part, through nitric oxide pathway as well as antioxidant, anti-inflammatory, and anti-apoptotic activities.