<p>The endoplasmic reticulum (ER) and mitochondria are fundamental organelles that govern a wide array of cellular processes and maintain intracellular homeostasis through highly specialized and interconnected functions. Their intimate structural and functional coupling at mitochondria-associated membranes (MAMs) enables the regulated exchange of Ca²⁺, lipids, and metabolites, thereby coordinating key physiological processes. Accumulating evidence underscores the critical role of ER-mitochondrial communication in the maintenance of intracellular Ca²⁺ homeostasis. Traumatic brain injury (TBI), however, disrupts this finely tuned inter-organelle crosstalk, triggering a complex cascade of pathological events characterized by Ca²⁺ dysregulation, ER stress, impaired protein folding, mitochondrial dysfunction, and activation of cell death pathways. This review provides a comprehensive synthesis of current knowledge on MAM-mediated Ca²⁺ transport and delineates how its dysregulation exacerbates cellular stress responses following TBI. We examine the contribution of Ca²⁺ imbalance to ER stress signalling, protein misfolding, and the pathological shift toward excessive mitochondrial fission, culminating in compromised bioenergetics and loss of cellular integrity. Furthermore, we discuss Ca²⁺ dysregulation-driven cell death mechanisms in the injured brain and evaluate emerging therapeutic strategies to restore MAMs function and Ca²⁺ signalling. Collectively, the interplay between Ca²⁺ dysregulation, ER stress, and mitochondrial dysfunction emerges as a central axis underlying neuronal loss after TBI. Elucidating these mechanisms may inform the development of targeted interventions to mitigate secondary injury and preserve neuronal function following TBI.</p>