Posttraumatic stress disorder (PTSD) is a highly disabling psychiatric condition that may arise after exposure to acute and severe trauma. It is a highly prevalent mental disorder worldwide, and the current treatment options for these patients remain limited due to low effectiveness. The time window right after traumatic events provides clinicians with a unique opportunity for preventive interventions against potential deleterious alterations in brain function that lead to PTSD. Some studies pointed out that PTSD patients present an abnormal function of the hypothalamic-pituitary-adrenal axis that may contribute to a vulnerability toward PTSD. Moreover, glucocorticoids have arisen as a promising option for preventing the disorder's development when administered in the aftermath of trauma. The present work compiles the recent findings of glucocorticoid administration for the prevention of a PTSD phenotype, from human studies to animal models of PTSD. Overall, glucocorticoid-based therapies for preventing PTSD demonstrated moderate evidence in terms of efficacy in both clinical and preclinical studies. Although clinical studies point out that glucocorticoids may not be effective for all patients' subpopulations, those with adequate traits might greatly benefit from them. Preclinical studies provide precise insight into the mechanisms mediating this preventive effect, showing glucocorticoid-based prevention to reduce long-lasting behavioral and neurobiological abnormalities caused by traumatic stress. However, further research is needed to delineate the precise mechanisms and the extent to which these interventions can translate into lower PTSD rates and morbidity.