The current study was conducted to investigate the possible ameliorative role of zinc nanoparticles (Zn NPs) against silver nanoparticles (Ag NPs)-induced oxidative and apoptotic brain damage in adult male rats. Twenty-four mature Wistar rats were randomly and equally divided into four groups: control group, Ag NPs group, Zn NPs group, and Ag NPs + Zn NPs group. Rats were exposed to Ag NPs (50 mg/kg) and/or Zn NPs (30 mg/kg) daily by oral gavage for 12 weeks. The results revealed that exposure to Ag NPs significantly increased malondialdehyde (MDA) content, decreased catalase and reduced glutathione (GSH) activities, downregulated the relative mRNA expression of antioxidant-related genes (Nrf-2 and SOD), and upregulated the relative mRNA expression of apoptosis-related genes (Bax, caspase 3 and caspase 9) in the brain tissue. Furthermore, severe neuropathological lesions with a substantial increase in the caspase 3 and glial fibrillary acidic protein (GFAP) immunoreactivity were observed in the cerebrum and cerebellum of Ag NPs-exposed rats. Conversely, co-administration of Zn NPs with Ag NPs significantly ameliorated most of these neurotoxic effects. Collectively, Zn NPs can be used as a potent prophylactic agent against Ag NPs-induced oxidative and apoptotic neural damage.