The therapeutic response to traumatic brain injury (TBI) still lacks a strategy to treat its acute and chronic phases. Given that TBI affects the lives of 1.5 million people a year, and the management of its early stages has significant effects on outcome, identifying a druggable target to mitigate damage could protect the cognitive and motor function of patients. Given the value of rescuing cells during TBI and of the health of mitochondria in preventing cell death, it is important to explore means of preventing mitochondrial stress. There is a growing body of evidence that identifies a role for androgens (i.e., testosterone and its derivative, dihydrotestosterone) in both this TBI pathology and managing mitochondrial stress. Androgen signaling is involved in regulating gene expression of several proteins that interact with key mitochondrial pathways, and since TBI alters androgen signaling in time-specific stages, it appears to be a promising target for a druggable intervention. In this review, we discuss the physiopathological events underlying TBI pathology, focusing especially on the impact inflammatory cascade has on disrupting cell function and the integrity of mitochondrion. Finally, we propose that the administration of androgens might be considered a promising pharmacological approach to alleviate inflammation and mitochondria impairment post-TBI.