Traumatic brain injury (TBI) is a major cause of death and disability throughout the world. In recent years, researchers focused on the pathological significance of calcium accumulation in the brain after TBI. Neuronal calcium homeostasis disturbances may result in the activation of calpain a ubiquitous calcium-sensitive protease. The calpain family has a well-established causal role in neuronal cell death following acute brain injury: their activation has been observed to progressively increase after either contusive or diffuse brain trauma in animals, suggesting calpain to be a mediator of early neuronal damage. We hypothesize that pretreatment with the calpain inhibitors in population at objective risk (military soldiers’ pre combat) in appropriate dose would open therapeutic time window expected to prevent and reduce extensive brain damage by providing optimal TBI neuroprotection. Additional therapeutic strategy for TBI, based on calpain modulating actions such as pretreatment with calpain inhibitors has been proposed. Since calpain overexpression has been well established in acute neuronal injury and further subsequent neurodegeneration, from a clinical viewpoint, we speculate that if this hypothesis proves correct pre-treatment inhibitors introduction may become a therapeutic option for different brain pathologies to be approached and treated with.