Cisplatin and oxaliplatin are widely used anticancer drugs. Their use is restricted by their dose-limiting side effects: nephrotoxicity and neurotoxicity, respectively. Cerium oxide nanoparticles (CONPs) are promising antioxidant and anti-inflammatory agent. To test the possible ameliorative impact of CONPs on the toxic effect of cisplatin and oxaliplatin in male albino rats. Forty eight rats were divided into 6 groups: control group, CONPs group, cisplatin group, cisplatin and CONPs group, oxaliplatin group, and oxaliplatin and CONPs group. After 4 weeks, serum urea and creatinine, renal tissue level of interleukin 10 (IL10), and total antioxidant (TAO) were measured in control, CONPs, and cisplatin groups. The other kidney was used for histopathological and immunohistochemical studies. The right sciatic nerves and the lumbar spinal cord of rats from control, CONPs, and oxaliplatin groups were used for immunohistochemical evaluations of nitrotyrosine, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP). Cisplatin significantly increased serum urea and creatinine levels, significantly decreased the kidney level of IL10 and TAO with marked tubular necrosis, hemorrhage and renal damage. Also, it decreased IL10 immunohistochemical expression. CONPs significantly decreased the serum urea and creatinine level and increased IL10 and TAO with lower renal damage and strong IL10 expression compared with cisplatin group. Oxaliplatin significantly decreased MBP immunoreactivity and increased nitrotyrosine immunoreactivity. In the lumbar spinal cord, GFAP immunoreactivity was significantly increased. CONPs significantly increased MBP and decreased nitrotyrosine immunoreactivity. GFAP immunoreactivity was significantly decreased. CONPs ameliorated cisplatin and oxaliplatin primary toxicities through anti-inflammatory and antioxidant characteristics.