Traumatic brain injury (TBI) is a significant and prevalent condition affecting the central nervous system (CNS). The complex pathophysiology of TBI involves glutamate excitotoxicity, inflammation, demyelination, programmed cell death, and edema. Glial cells, particularly astrocytes and microglia, play crucial roles in the response to TBI, leading to glial scar formation and tissue repair. However, this scar can also hinder complete tissue recovery, causing permanent scarring and functional impairments. Recent advancements in transcriptomic and proteomic analyses have revealed that glial cells, including astrocytes and microglia, are heterogeneous populations with distinct genomic and functional characteristics. These differences influence their roles in neurodegeneration, neuroprotection, and regeneration. The severity, region, and timing of TBI determine the outcome, with varying effects on different brain structures. This review highlights the complex nature of TBI, emphasizing the importance of glial cells in post-injury processes and the need for further research to understand and potentially improve therapeutic approaches. Key topics discussed include intercellular signaling, long-term impacts of TBI, and novel therapeutic strategies.Traumatic brain injury (TBI) is a significant and prevalent condition affecting the central nervous system (CNS). The complex pathophysiology of TBI involves glutamate excitotoxicity, inflammation, demyelination, programmed cell death, and edema. Glial cells, particularly astrocytes and microglia, play crucial roles in the response to TBI, leading to glial scar formation and tissue repair. However, this scar can also hinder complete tissue recovery, causing permanent scarring and functional impairments. Recent advancements in transcriptomic and proteomic analyses have revealed that glial cells, including astrocytes and microglia, are heterogeneous populations with distinct genomic and functional characteristics. These differences influence their roles in neurodegeneration, neuroprotection, and regeneration. The severity, region, and timing of TBI determine the outcome, with varying effects on different brain structures. This review highlights the complex nature of TBI, emphasizing the importance of glial cells in post-injury processes and the need for further research to understand and potentially improve therapeutic approaches. Key topics discussed include intercellular signaling, long-term impacts of TBI, and novel therapeutic strategies.