The main obstacle to cisplatin's efficacy in cancer chemotherapy is neurotoxicity. The objective of this study was to create and characterize amifostine (AMF)-loaded silica nanoparticles (SiNPs@AMF), and investigate the cytoprotective effects of this nano-emulsion model of AMF against cisplatin-induced neurotoxicity in male albino rats. The nano-emulsion was prepared using cetyltrimethyl ammonium bromide (CTAB), castor oil (CAO), tetraethyl orthosilicate (TEOS), and amifostine (AMF) as extra stabilizing agent, surfactant, sources for silica, and a model drug, respectively. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to analyse the hydrodynamic average size and particle shape of the produced nano-emulsion of silica and SiNPs@AMF. It was evident that when compared to silica nano-emulsion, the prepared SiNPs@AMF slightly enhanced the particle size. Biomarkers of oxidative stress including malondialdehyde (MDA), nitric oxide (NO), paraoxonase-1 (PON-1) as well nuclear factor kappa B (NF-κB) were determined. Histopathological examination of brain was also done. Results indicated that MDA , NO and NF-κB levels were increased whereas PON-1 decreased following cisplatin injection.The administration of SiNPs@AMF protected against cisplatin-induced histopathological changes. Treatment with SiNPs@AMF returned these alterations to their original state. Our findings suggest that oxidative stress is involved in the neurotoxic effects of cisplatin and the cytoprotective action of SiNPs@AMF ameliorate the neurotoxic effect induced by cisplatin.