Post-traumatic stress disorder (PTSD) is a well-known psychiatric disorder that affects millions of people worldwide. Pharmacodynamic and cognitive-behavioral therapies (CBT) have been used to treat patients with PTSD. However, it remains unclear whether there are concurrent changes in psychopathological and neurophysiological factors associated with PTSD patients. Past reports described those PTSD patients with efficient fatty acid metabolism, neurogenesis, mitochondrial energy balance could improve ability to cope against the conditioned fear responses and traumatic memories. Furthermore, cognitive, behavioral, cellular, and molecular evidence can be combined to create personalized therapies for PTSD sufferers either with or without comorbidities such as depression or memory impairment. Unfortunately, there is still evidence lacking to establish a full understanding of the underlying neurophysiological and psychopathological aspects associated with PTSD. This review has extensively discussed the single nucleotide polymorphism (SNPs) of genetic factors to cause PTSD, the implications of inflammation, neurotransmitter genomics, metabolic alterations, neuroendocrine disturbance (hypothalamus-pituitary-adrenal (HPA) axis), mitochondrial dynamics, neurogenesis, and premature aging related to PTSD-induced psychopathology and neurophysiology. In addition, the review delineated the importance of CBT and several pharmacodynamic therapies to mitigate symptomatology of PTSD.