Aim of the study: The goal of the current study was to evaluate the protective impact of chitosan nanoparticles (COS-NPs) against monosodium glutamate (MSG)-induced oxidative stress in submandibular salivary glands and genotoxicity of bone marrow chromosomes. Material and methods:  30 adult male albino rats were randomly divided into three equal groups and treated orally for 24 days as follow: Group I the (control) group, group II (MSG-treated group): each rat received a daily MSG at a dose of (400mg/Kg. b. w.) and group III: (MSG + COS-NPs treated group): rats treated orally with monosodium glutamate (400 mg/kg. b. w.) then the chitosan nanoparticles (280 mg/kg b. w.) respectively was administered to rats daily by oral gavage. After 24 days, both sides of the submandibular salivary glands were excised, processed and  finally inspected histologically and immunohistochemically. Bone marrow was obtained from both femora of rats, 500 well spread metaphases per each animal were checked microscopically for both structural and numerical chromosomal aberrations. Results: The submandibular salivary glands (SMSG) of MSG treated rats revealed severe histopathological changes, moderate to strong granular cytoplasmic reaction of caspase-3 immunoreactivity in the acinar and ductal cells. And increase in the frequency of structural and numerical chromosomal aberrations of bone marrow cells. Chitosan nanoparticles (COSNPs) exhibited significant amelioration in histological and immunohistochemical picture in the submandibular salivary glands of MSG treated rats. Also chitosan nanoparticles could significantly inhibit the chromosomal aberrations and succeeded to neutralize the MSG genotoxic effects in bone marrow cells of rats. Conclusion: It could be concluded that COS-NPs have potential antioxidant effect that protect against cytotoxicity and genotoxicity induced by MSG in rats.