BackgroundWith the recent growth in the applications of silver nanoparticles (Ag-NPs), worries about their harmful effects are increasing. Selenium plays a vital role in the antioxidant defense system as well as free radical scavenging activity. ObjectivesThis study aims to inspect the neuroprotective effect of selenium-loaded chitosan nanoparticles (CS-SeNPs) against the adverse impact of Ag-NPs on brain tissue in adult rats. DesignRats were divided into four groups: group I (control) was administered distilled water (0.5 mL/kg), group II was administered Ag-NPs (100 mg/kg), group III was administered Ag-NPs (100 mg/kg) and CS- SeNPs (0.5 mg/kg) and group IV received only CS- SeNPs (0.5 mg/kg) daily by oral gavage. After 60 days, rats were subjected to behavioral assessment and then euthanized. Brain tissues were obtained for estimation of total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2-deoxy Guanosine (8-OHdG), and Nuclear Factor Erythroid 2 Like Protein 2 (Nrf2). Also, histological examination of the brain and immunohistochemical detection of glial fibrillary acidic protein (GFAP) were investigated Resultsexposure to Ag-NPs induced marked neurotoxicity in the brain tissue of rats that was manifested by decreased levels of TAC and Nrf2 with increased levels of MDA and 8-OHdG. Also, various pathological lesions with an increase in the number of GFAP immunoreactive cells were detected. While brain tissue of rats received Ag-NPs plus CS-SeNPs group (III) revealed significantly fewer pathological changes. ConclusionCo-administration of CS-SeNPs significantly ameliorates most of the Ag-NPs-induced brain damage.