【】Objective: To explore the neuroprotective effect of trigeminal nerve stimulation (TNS) on hypoxic-ischemic encephalopathy (HIE) and its potential mechanism. Methods: Seven-day-old neonatal SD rats were used to establish the HIE model, and the rats were randomly divided into the control group, HIE model group (model group), TNS intervention group (model + TNS group), and TNS + glutamate transporter 1 (GLT1) inhibitor group (HIE + TNS + Dihydrokainic acid group). Short-term and long-term neurobehavior were evaluated by negative geotaxis test and rotarod test. TTC staining, HE staining, qRT-PCR, Western blot, and ELISA were used to quantify ischemic brain lesion volume, pathological damage of brain tissue, expression level of GLT1, levels of endoplasmic reticulum stress (ERS)-related proteins, and levels of inflammatory factors, respectively. Results: The model group showed severe cerebral infarction, with neuronal swelling, nuclear pyknosis, intensely stained cytoplasm and extensive infiltration of inflammatory cells. Compared with the control group, the model group had a significantly decreased expression level of GLT1, a significantly increased time required to turn 180 degrees, a significantly shortened fall-off time, and a significantly increased expression of glucose-regulated protein 78 (GRP78) (P<0.05). Compared with the model group, the model + TNS group had an increased expression level of GLT1, a significantly shortened time required to turn 180 degrees, a significantly prolonged fall-off time, and significantly decreased expressions of GRP78 and levels of tumor necrosis factor-α (TNF-α) (P<0.05). Compared with the model + TNS group, the model + TNS + Dihydrokainic acid group had aggravated cerebral infarction, a decreased expression level of GLT1, and significantly increased levels of TNF-α and expression of GRP78 (P<0.05). Conclusion: TNS exerts a neuroprotective effect on HIE by up-regulating the expression of GLT1 and inhibiting the ERS-mediated neuronal apoptosis pathway.