Introduction: Long-duration space missions expose astronauts to extreme conditions such as microgravity, cosmic radiation, prolonged isolation, confinement, and sleep-wake cycle disruptions. These factors trigger a complex physiological response mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for the endocrine regulation of stress. Persistent activation of this axis can lead to metabolic, immunological, and neurocognitive changes that compromise crew performance. In this context, cortisol has been proposed as a useful biomarker for assessing physiological adaptation during spaceflight. Objective: To describe HPA axis alterations observed during space missions and to analyze the role of cortisol as a potential biomarker for functional impairment and operational risk in long-duration flights. Methodology: A narrative review of the available scientific literature on space endocrinology, stress physiology, and human adaptation to microgravity was conducted. The review included studies involving astronauts, prolonged bed-rest models, confinement simulations, and space-analog environments, focusing on HPA axis modifications and cortisol levels. Results: Available evidence indicates that prolonged exposure to the space environment induces significant alterations in HPA axis regulation.