Monosodium glutamate (MSG) is used as a avor, and a taste enhancer was reported to evoke marked neuronal impairments. This study investigated the neuroprotective ability of avonoid apigenin against neural damage in MSG-administered rats. Adult male rats were allocated into four groups; control, apigenin (20 mg/kg, orally), MSG (4 g/kg, orally), and apigenin + MSG at the aforementioned doses for 30 days. Regarding the levels of neurotransmitters, our results revealed that apigenin augmented the activity of acetylcholinesterase (AChE) markedly, and levels of brain monoamines (dopamine, norepinephrine, and serotonin) accompanied by lessening the activity of monoamine oxidase (MAO) as compared to MSG treatment. Moreover, apigenin counteracted the MSG-mediated oxidative stress by decreasing the malondialdehyde (MDA) levels together with elevating the glutathione (GSH) levels. In addition, pretreatment with apigenin induced notable increases in the activities of cortical superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Further, apigenin attenuated the cortical in ammatory stress as indicated by lower levels of pro-in ammatory mediators as interleukin-1 b (IL-1b), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) as well as downregulated inducible nitric oxide synthase (iNOS) expression levels. Histopathological screening validated the abovementioned results and revealed that apigenin restored the distorted cytoarchitecture of the brain cortex. Thus, the present ndings collectively suggest that apigenin exerted signi cant protection against MSG-induced neurotoxicity by enhancing the cellular antioxidant response and attenuating in ammatory machineries in the rat brain cortex.