Traumatic brain injury is a global health crisis, causing significant death and disability worldwide. Neuroinflammation that follows traumatic brain injury has serious consequences for neuronal survival and cognitive impairments, with astrocytes involved in this response. Following traumatic brain injury, astrocytes rapidly become reactive, and astrogliosis propagates from the injury core to distant brain regions. Homeostatic astroglial proteins are downregulated near the traumatic brain injury core, while pro-inflammatory astroglial genes are overexpressed. This altered gene expression is considered a pathological remodeling of astrocytes that produces serious consequences for neuronal survival and cognitive recovery. In addition, glial scar formed by reactive astrocytes is initially necessary to limit immune cell infiltration, but in the long term impedes axonal reconnection and functional recovery. Current therapeutic strategies for traumatic brain injury are focused on preventing acute complications. Statins, cannabinoids, progesterone, beta-blockers, and cerebrolysin demonstrate neuroprotective benefits but most of them have not been studied in the context of astrocytes. In this review, we discuss the cell signaling pathways activated in reactive astrocytes following traumatic brain injury and we discuss some of the potential new strategies aimed to modulate astroglial responses in traumatic brain injury, especially using cell-targeted strategies with miRNAs or lncRNA, viral vectors, and repurposed drugs.