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Although biomedical approaches commonly appear in the literature, considering psychological and social factors alongside physiologic health offers a more holistic approach to astronaut care. Integrating the biopsychosocial (BPS) framework into medical planning addresses complex spaceflight challenges and aids in developing mitigation strategies. This review examined health risks associated with long-duration spaceflight within a BPS framework. Sources included governmental space agencies, academic textbooks, and relevant publications from multiple databases. Considering the National Aeronautics and Space Administration's Human Research Program's 5 main hazards, a conceptual model was developed to highlight the multifactorial BPS effects of spaceflight. In space, astronauts face unique environments and biological adaptations, including fluid shift, plasma volume loss, bone density loss, and muscle atrophy. Noise and the absence of natural light disrupt circadian rhythms, causing sleep disturbances and fatigue, which affect physical and mental health. Studies on crews in isolated and confined extreme environments reveal psychosocial challenges, including impaired mood and cognition, interpersonal tension, and miscommunication. International collaboration in spaceflight introduces differences in communication, problem solving, and social customs due to diverse cultural backgrounds. Upcoming long-distance missions likely will amplify these challenges. This review emphasizes BPS health considerations in long-duration spaceflight. 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