<p>Traumatic brain injury (TBI) is a significant global public health issue, affecting millions annually. Excessive calcium influx in neurons and astrocytes triggers a cascade of neurotoxic events, including mitochondrial dysfunction, increased production of reactive oxygen species, and hypometabolism, all of which contribute to impaired neurological function. Following TBI, alterations in presynaptic voltage-gated calcium channels (VGCCs) and the formation of plasma membrane pores facilitate Ca²⁺ influx, membrane depolarization, and an increased vesicular release of glutamate and Ca²⁺ into the synaptic cleft. This leads to the overactivation of NMDA receptors and the propagation of neurotoxic Ca²⁺ signals to neighboring neurons, further spreading neurobiochemical disruptions. Given this, blocking Ca²⁺ influx may mitigate excitotoxicity, and mitochondrial alterations caused by TBI. Among the pathways involved in Ca²⁺ cytotoxicity, the alpha-2-delta (α₂δ_(1–2)) subunit of VGCCs, located at the presynaptic terminal, remains the least explored. In this review, we briefly examine the pathophysiological hallmarks of TBI and their connection to Ca²⁺ dysregulation, while exploring the distribution of VGCC subtypes in the brain. Additionally, we highlight pregabalin, an analog of gabapentin and a selective antagonist of the α₂δ_(1–2) subunit, as a promising therapeutic strategy to counteract Ca²⁺-induced neurotoxicity following TBI.</p>