An increasing number of studies indicate that environmental conditions and experiences encountered in the daily life of individuals can dramatically impact the capacity of the brain to resist challenges associated with injury, toxicity, or disease. Diet and exercise management have become a realistic possibility that can be easily implemented to reduce the burden of traumatic brain injury (TBI). This chapter discusses current advances in the understanding of the molecular mechanisms by which diet and exercise influence brain function and plasticity during homestatic conditions and after TBI. Abundant evidence in humans supports the effects of diet and exercise on maintaining normal brain function and reducing the incidence of neurodegenerative disorders. TBI compromises mitochondrial bioenergetics, as well as a wide range of molecular systems important for energy homeostasis, which suggests that the TBI brain is vulnerable to metabolic disorders. Brain-derived neurotrophic factor (BDNF) is one of the most influential molecules for maintaining brain function and plasticity.