<p>Traumatic brain injury (TBI) to the motor cortex disrupts corticospinal tracts and induces persistent sensorimotor impairments, largely driven by secondary neurobiochemical cascades. Excessive synaptic glutamate release, mitochondrial Ca²⁺ overload, and progressive neurodegeneration critically shape these outcomes, with preclinical and clinical data revealing neuronal loss and proteinopathy resembling motor neuron disorders. Here, we investigated whether pregabalin blockade of the presynaptic α₂δ_1-2 subunit of voltage-gated Ca²⁺ channels could mitigate excitotoxicity and promote sensorimotor recovery after TBI. Mice subjected to controlled cortical impact (CCI) received daily pregabalin (i.p., 60 mg.kg^-1) or saline for 10 days, and neurobehavioral performance was assessed at 24&#xa0;h, 11-, and 12-days post-injury. In addition to robust and persistent deficits detected by the modified neurological severity score (mNSS), complementary tests including open field, grip strength, cylinder, wire-hanging, and inverted screen, captured sensitive impairments in corticospinal integrity and global motor function. Pregabalin treatment downregulated α₂δ₂ subunit expression, reduced cerebrospinal fluid glutamate levels, and restored mitochondrial Ca²⁺ handling by improving influx–efflux dynamics through Na⁺/Ca²⁺ exchange. At the molecular level, pregabalin decreased hallmarks of neurodegeneration, including Cyclin dependent kinase 5, Tau^Ser396 hyperphosphorylation, caspase-12, and caspase-3 within synaptic terminals. These neuroprotective effects translated into significant improvements in both mNSS and multidimensional sensorimotor outcomes following TBI. Together, our findings confirm the neurodegenerative trajectory underlying TBI-induced neuromotor deficits and highlight the presynaptic α₂δ_1–2 subunit antagonism as a promising therapeutic target to mitigate long-term neurological sequelae.</p>