Concussion presents a fundamental biological paradox. Although the initiating mechanical injury lasts only milliseconds, neurological dysfunction may evolve over months or years, leading to persistent cognitive, emotional, and behavioral impairment. Repetitive concussions further increase the risk of chronic traumatic encephalopathy (CTE) and other neurodegenerative disorders, yet the mechanisms linking a transient biomechanical insult to progressive neurological disease remain poorly understood. Here we introduce the Calpain Homeostasis Model (CHM), a unifying conceptual framework proposing that persistent disruption of calpain homeostasis provides the mechanistic link between the initial injury and delayed neurological dysfunction. Under physiological conditions, calpain-1 and calpain-2 coordinate adaptive proteolytic remodeling while preserving neuronal homeostasis. Following concussion, sustained calcium dysregulation and injury-induced signaling shift the physiological balance toward persistent calpain-2 activation, converting adaptive remodeling into maladaptive proteolysis and initiating self-amplifying cycles of cellular dysfunction. Within this framework, excitotoxicity, mitochondrial dysfunction, oxidative stress, proteostatic failure, neuroinflammation, and synaptic degeneration are viewed as interconnected manifestations of the sequential collapse of neuronal homeostasis rather than independent pathological processes. The CHM provides a mechanistic explanation for the temporal dissociation between the brief mechanical injury and the prolonged evolution of neurological dysfunction. It also establishes a translational framework in which calpain-derived proteolytic fragments serve as biomarkers of pathological calpain activation, while restoration of calpain homeostasis—particularly through selective calpain-2-derived inhibition—represents a promising disease-modifying therapeutic calpain-2 strategy.