<p>Blast-induced traumatic brain injury (blast TBI) causes diffuse neuropathology, blood-brain barrier disruption, and complex neurological sequelae. Mitochondrial dysfunction is increasingly recognized as a contributor to secondary injury cascades and has been associated with bioenergetic impairment, alterations in mitochondrial dynamics, oxidative stress, and apoptotic signaling following blast exposure. Primary data from our recent study demonstrates acute TCA cycle impairment and supports a framework of glycolytic shift in the brain alongside a bottleneck of key TCA cycle intermediates. This review also examines current literature on mitochondrial pathophysiology across neurons, astrocytes, and endothelial cells after blast TBI. We highlight cumulative data detailing disruptions in mitochondrial quality control, including fission–fusion imbalance, and altered mitophagy, as well as bioenergetic dysfunction, calcium dysregulation, enzymatic alterations, and oxidative damage. The influence of lifestyle and environmental modifiers on brain mitochondrial health and how it can alter long-term outcomes after blast TBI are also discussed. We further discuss therapeutic strategies, including mild mitochondrial uncouplers, modulators of mitochondrial dynamics, and mitochondrial transplantation, aimed at preserving mitochondrial integrity and function. Collectively, these findings demonstrate that mitochondrial dysfunction is an important component of blast TBI pathophysiology and supports continued investigation of approaches that integrate modifying factors and therapeutic strategies to improve outcomes after blast TBI.</p>