Mitochondria are multifunctional organelles involved in varied cellular processes. Mitochondria cooperate and integrate hormonal, metabolic, and molecular intracellular signaling pathways to maintain cellular homeostasis. Cellular stress response depends on the mitochondrial capacity to maintain energy and metabolic stability. Here we discuss several potential mechanisms by which mitochondrial dysfunction may contribute to posttraumatic stress disorder (PTSD) severity. Mitochondrial dysfunction plays an important role in disease progression through the regulation of adenosine triphosphate (ATP) production, Ca2+ homeostasis, or reactive oxygen species generation. Current research suggests that stress exposure results in alterations in mitochondria contributing to impaired energetics, cell signaling, and hormone production promoting health complications. We describe several compounds with antioxidant properties that have demonstrated significant amelioration of abnormal pathological and behavioral manifestations in PTSD. Targeting mitochondrial bioenergetics is the primary mode of action of therapeutic compounds in PTSD.