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Background Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE. Aims To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis. Methods We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance. Results TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective. Discussion Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment. Conclusion It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.