Background: Monosodium glutamate (MSG), a sodium salt of l-glutamic acid, is used in many different types of cuisine to improve flavor and palatability. Food containing MSG was associated with excitotoxicity which induced oxidative stress and neuroinflammation; the most common mechanism that linked with neurological disorders. Attention-deficit/ hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects children most frequently around the globe. Sesamol (SML) is one of the promising bioactive flavonoids with multiple pharmacological activities. Objective: we aim to examine the potential neuroprotective effects of sesamol against MSG by modulating the GSK3-/Nrf2/NF-k/Bcl-2 pathways. Materials and Methods: thirty-six male young rats (4-6 weeks old) were randomly distributed over three groups, (12/group). Control group (1): rats received 2% DMSO in saline. ADHD group (2): rats received 400mg/kg MSG daily by intra-gastric tube for 8 consecutive weeks. ADHD + SML group (3): rats treated like group 2, in addition to receiving SML (20mg/kg i.p.) in concurrent with MSG. behavioral tests (y-maze and open field test) were conducted over the final four days of the 8-week trial and after the experiment's conclusion rats were sacrificed and Biochemical parameters were measured in brain tissue (assessment of brain monoamines, GSK3-β, Nrf2, SOD, inflammatory, and apoptotic biomarkers by ELISA technique along with colorimetric assay of Calcium, MDA, SOD and TAC level). Conclusion: According to our results, SML may be able to protect the brain from neurological disorders resembling ADHD by targeting the GSK3-β/Nrf2/NF-kβ/Bax/Bcl-2 signaling pathways.