Attention deficit hyperactivity disorder (ADHD) has high incidence rate among children which may be due to excessive monosodium glutamate (MSG) consumption and social isolation (SI). We aimed to explore the relationships between MSG, SI, and ADHD development and to evaluate the neuroprotective potential of Punicalagin (PUN). Eighty male rat pups randomly distributed into eight groups. Group I is the control, and Group II is socially engaged rats treated with PUN. Groups III to VII were exposed to ADHD-inducing factors: Group III to SI, Group IV to MSG, and Group V to both SI and MSG. Furthermore, Groups VI to VIII were the same Groups III to V but additionally received PUN treatment. Exposure to MSG and/or SI led to pronounced behavioral anomalies, histological changes and indicative of ADHD-like symptoms in rat pups which is accompanied by inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme-oxygenase 1 (HO-1)/Glutathione (GSH) pathway, decline of the brain-derived neurotrophic factor (BDNF) expression and activation of the Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-kB)/NLR Family Pyrin Domain Containing 3 (NLRP3) pathway. This resulted in elevated inflammatory biomarker levels, neuronal apoptosis, and disrupted neurotransmitter equilibrium. Meanwhile, pretreatment with PUN protected against all the previous alterations. We established compelling associations between MSG consumption, SI, and ADHD progression. Moreover, we proved that PUN is a promising neuroprotective agent against all risk factors of ADHD.