Reactive gliosis in traumatic brain injury (TBI) is a complex process involving glial cells, particularly astrocytes and microglia, which respond to tissue damage by activating, hypertrophying, and proliferating, leading to the formation of a glial scar. This scar serves as a protective barrier in the acute phase but can hinder tissue recovery in the chronic phase by causing permanent scarring. The process involves various glial cell types, with astrocytes and microglia playing key roles in neuroinflammation, edema, and neuroprotection. Recent studies using advanced technologies like transcriptomic and proteomic analyses have shown that astrocytes and microglia are heterogeneous cell populations with distinct genomic and functional characteristics, contributing to neurodegeneration, neuroprotection, and regeneration. The severity, region, and time-dependent nature of TBI outcomes are influenced by the model of injury and the distance from the lesion site. This review discusses findings on intercellular signaling, long-term impacts of TBI, and novel therapeutic approaches. It emphasizes the importance of studying glial cells in TBI to improve research and model selection. TBI is a common condition with significant medical and socio-economic impacts, affecting millions globally. It involves primary and secondary injuries, with secondary injury resulting from cellular reactions, neuroinflammation, edema, and hypoxia. The Glasgow Coma Scale (GCS) is used to classify TBI severity. TBI research focuses on glial cells, including astrocytes, microglia, and oligodendrocytes, with various experimental models such as weight drop (WD), controlled cortical impact (CCI), fluid percussion injury (FPI), blast injury (BI), penetrating ballistic-like brain injury (PBBI), and closed-head impact model of engineered rotational acceleration (CHIMERA). These models help study TBI mechanisms and outcomes. Glial cells respond to TBI by undergoing reactive gliosis, leading to edema, excitotoxicity, and neuroinflammation. Edema can be vasogenic or cytotoxic, with cytotoxic edema resulting from cellular swelling and ion imbalances. Excitotoxicity involves excessive activation of glutamate receptors, leading to calcium influx and neuronal apoptosis. Neuroinflammation is a critical response, with microglia and astrocytes playing key roles. Microglia release pro-inflammatory cytokines and chemokines, while astrocytes contribute to neuroinflammation through glutamate transport and cytokine production. NG2-glia also play a role in neuroinflammation, influencing microglial activity and homeostasis. Understanding these processes is essential for developing therapeutic strategies for TBI.Reactive gliosis in traumatic brain injury (TBI) is a complex process involving glial cells, particularly astrocytes and microglia, which respond to tissue damage by activating, hypertrophying, and proliferating, leading to the formation of a glial scar. This scar serves as a protective barrier in the acute phase but can hinder tissue recovery in the chronic phase by causing permanent scarring. The process involves various glial cell types, with astrocytes and microglia playing key roles in neuroinflammation, edema, and neuroprotection. Recent studies using advanced technologies like transcriptomic and proteomic analyses have shown that astrocytes and microglia are heterogeneous cell populations with distinct genomic and functional characteristics, contributing to neurodegeneration, neuroprotection, and regeneration. The severity, region, and time-dependent nature of TBI outcomes are influenced by the model of injury and the distance from the lesion site. This review discusses findings on intercellular signaling, long-term impacts of TBI, and novel therapeutic approaches. It emphasizes the importance of studying glial cells in TBI to improve research and model selection. TBI is a common condition with significant medical and socio-economic impacts, affecting millions globally. It involves primary and secondary injuries, with secondary injury resulting from cellular reactions, neuroinflammation, edema, and hypoxia. The Glasgow Coma Scale (GCS) is used to classify TBI severity. TBI research focuses on glial cells, including astrocytes, microglia, and oligodendrocytes, with various experimental models such as weight drop (WD), controlled cortical impact (CCI), fluid percussion injury (FPI), blast injury (BI), penetrating ballistic-like brain injury (PBBI), and closed-head impact model of engineered rotational acceleration (CHIMERA). These models help study TBI mechanisms and outcomes. Glial cells respond to TBI by undergoing reactive gliosis, leading to edema, excitotoxicity, and neuroinflammation. Edema can be vasogenic or cytotoxic, with cytotoxic edema resulting from cellular swelling and ion imbalances. Excitotoxicity involves excessive activation of glutamate receptors, leading to calcium influx and neuronal apoptosis. Neuroinflammation is a critical response, with microglia and astrocytes playing key roles. Microglia release pro-inflammatory cytokines and chemokines, while astrocytes contribute to neuroinflammation through glutamate transport and cytokine production. NG2-glia also play a role in neuroinflammation, influencing microglial activity and homeostasis. Understanding these processes is essential for developing therapeutic strategies for TBI.