Excessive stimulation of ionotropic glutamate receptor is associated with glutamate-mediated excitotoxicity, thereby causing oxidative imbalance and mitochondrial dysfunction, resulting in the excitotoxic death of neurons. Eminent role of endoplasmic reticulum under glutamate-induced excitotoxicity has been highlighted in numerous literatures which have been observed to trigger endoplasmic reticulum stress (ER stress) as well as regulating oxidative stress. However, combating ER stress in excitotoxic neurons can provide a novel approach to alleviate the mitochondrial dysfunctioning and ROS generation. Therefore, we propose to investigate the cross-communication of α-amino-3-hydroxy-5-methyl-4-isoxzole-propionate (AMPA) excitotoxicity-induced oxidative injury with ER stress by employing ER stress inhibitor-4-phenlybutyric acid (4-PBA). Male SD rats were divided into four groups viz sham group (group 1), AMPA (10 mM)-induced excitotoxic group (group 2), curative group of AMPA-induced excitotoxic animals given 4-PBA at a dose of 100 mg/kg body weight (group 3), and alone 4-PBA treatment group (100 mg/kg body weight) (group 4). Animals were sacrificed after 15 days of treatment, and hippocampi were analyzed for histopathological examination, ROS, inflammatory markers, mitochondrial dysfunction, and ER stress markers. AMPA-induced excitotoxicity exhibited a significant increase in the levels of ROS, upregulated ER stress markers, inflammation markers, and compromised mitochondrial functioning in the hippocampus. However, 4-PBA administration significantly curtailed the AMPA-induced excitotoxic insult. This study suggests that targeting ER stress with a chemical chaperone can provide a better therapeutic intervention for neurological disorders involving excitotoxicity, and thus, it opens a new avenue to screen chemical chaperones for the therapeutic modalities.