Costus afer leaf (Cost) extract used as traditional herbal therapy for various diseases. Long term treated with cyclosporine (CsA) concomitant with development of renaltoxicity. The current study aims to assess the nephroprotective mechaism effect of Cost in CsA nephrotoxic rats. Forty male rats were distributed into 4 groups; control (Cont), CsA; rats intraperitoneal (i.p) injected with CsA (twenty five mg/kg b.wt) for twenty one days, Cost 750 mg/ kg b.wt +CsA, Cost 1500 mg/ kg b.wt +CsA; rats received Cost orally for twenty one days, followed by i.p. injection with CsA. Biochemical samples were collected after 24 h from the last dose of CsA as well as renal tissue samples were collected for histopathogical examination. Renal oxidative stress biomarkers (lipid peroxides (MDA) and catalase (CAT)) and the serum anti-inflammatory biomarkers (tumor necrosis factor interleukin-1beta (IL-1β) and -alpha (TNF-α)) were derermined. Kindeny functions; serum levels of creatinine, uric acid and urea as well as serum ionic levels of sodium Na+ and potassim K+ were measured. The results of this study revealed that injection of CsA induced significant increased in renal MDA, serum anti-inflammatory cytokines (TNF-α and IL-1β), serum kidney function paramters and the serum ionic K+ levels, with significant decrease in the renal CAT and serum ionic Na+ compared with cont group. Renal tisuues showing congestion, focal hemorrhage and intesritial nephritis, with coagulating necrosis of the renal tubules in the CsA group. Oral adminstration of Cost extract significantly ameliorated CsA- induced renal oxidative stress. It reduced CsA-induced elevation in serum anti-inflammatory cytokines and kidney function parameters. as well as the changes in ionic Na+ and K+ levels compared with CsA group. It also protected against CsA-induced histopathological changes. Therefore, Cost extract ameliorates nephrotoxicity caused by CsA through antioxidant and anti-inflammatory mechanisms.