Cisplatin (Cis) is an anticancer drug, which is accompanied with major side effects including nephrotoxicity. The current study was performed to assess the possible prophylactic effects of fenofibrate (FEN), Nicotinamide (NAM) and their combination on oxidative stress and inflammatory cytokines associated with cisplatin-induced renal damage. Rats were randomly divided into seven groups (8 each) as follows; control group; FEN group (100 mg/kg/day p.o.); NAM group (200 mg/kg/day p.o.); FEN and NAM were administered for eight days. Cis group (7 mg/kg i.p. as a single dose on day five); FEN + Cis group; NAM + Cis group and FEN + NAM + Cis group. Urine, blood and kidneys were taken out for biochemical and histopathological analysis and scoring. Oxidative stress induced by Cis was evidenced by significant elevation in renal Malondialdehyde (MDA) level acompanied by significant decrease in Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) in kidney tissues. Moreover, Cis produced significant increase in kidney Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6), the proinflammatory cytokines and significant decrease in Interleukin-10 (IL-10), the anti-inflammatory cytokine. However, administration of either FEN or NAM attenuated cisplatin-induced increased oxidative stress and inflammation in the kidney of rats, associated with improvement of the impaired renal function and histopathological changes, but their combination was found to be more effective in protection against cisplatin-induced renal damage than each drug alone. In conclusion, FEN and NAM combination protected the kidney tissue against cisplatin- induced nephrotoxicity through their antioxidant and anti-inflammatory activities.