Long-duration space exploration represents one of the greatest physiological challenges for humankind. Prolonged exposure to microgravity, cosmic radiation, confinement, social isolation, and disruption of circadian rhythms generates a complex adaptive response in multiple biological systems. Among these, the hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the neuroendocrine regulation of stress. Sustained activation of this axis can induce metabolic, immunological, cardiovascular, and neurocognitive modifications with potential impacts on the operational performance and safety of space missions. Objective: To analyze the available scientific evidence on alterations of the HPA axis induced by microgravity and other factors associated with the space environment, as well as its usefulness as a model of extreme stress for future human exploration missions. Methodology: A narrative review of the published scientific literature on space medicine, endocrinology, and stress physiology was conducted. Studies in astronauts, models of prolonged bed rest, microgravity simulations, and analogous confinement environments used to reproduce the physiological conditions of long-duration spaceflight are included. Results: