Background Monosodium glutamate (MSG) is used extensively as a food additive in the diets of many countries around the world. Aim of the study Our aim was to determine the effects of green zinc oxide nanoparticles on MSG-induced oxidative damage, neurotransmitter changes, and histopathological alternation in the cerebral cortexes of rats. Methods MSG was administered orally at two doses of 6 and 17.5 mg/kg body weight. The higher dose was associated with a significant decline in the activities of superoxide dismutase, catalase, and glutathione peroxidase, as well as the levels of brain-derived neurotrophic factor (BDNF) and glutathione (GSH) in the cerebral cortex of rats. Results The administration of zinc oxide nanoparticles/green tea extract (ZnO NPs/GTE) to 17.5 mg/kg MSG-treated rats was associated with significant improvements in all parameters previously shown to be altered by MSG. The higher dose of MSG induced significant histopathological variation in brain tissue. Co-treatment of rats with ZnO NPs/GTE and MSG-HD inhibited the reduction of neurotransmitters and acetylcholinesterase by MSG. Conclusions ZnO NPs/GTE have the potential to protect against oxidative stress and neuronal necrosis induced by MSG-HD. ZnO NPs/GTE conferred a greater benefit than the control treatment or ZnO NPs or GTE administered separately.