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Space flights can produce physiological changes in the spine, leading to the development of acute and chronic pain in passengers. However, there is a lack of comprehensive literature exploring physiological spine changes and acute and chronic pain in space passengers (astronauts and animals). The first aim of this study was to identify the physiological changes experienced by passengers (humans and animals) after space flight. The second aim was to identify the incidence of low back pain during and after space flight. This systematic review was conducted following PRISMA guidelines and was pre-registered in PROSPERO (ID 451144). We included Randomized Controlled Trials or longitudinal studies in humans and animals, and the variables must be assessed either in-flight or post-flight. We conducted a literature search in major databases combining the keywords: Pain; Space; Low Back Pain; Astronauts; Spine Changes; Microgravity; Physiological Changes; Humans; Animals. Risk of bias and quality of studies were analyzed, and the level of evidence was assessed using the GRADE system. After duplicates were removed, 115 abstracts were screened by two reviewers, and finally, 11 articles were included in this review. The evidence indicates that astronauts experience muscle atrophy in the lumbar multifidus with a moderate to large effect, especially in the L4-L5 and L5-S1 segments. Space flights also decrease the range of motion with a moderate effect, along with disc herniations and disc dehydration. 77% of astronauts experience pain during spaceflight, and 47% develop acute pain after spaceflight. Chronic pain was reported by 33% of the astronauts. After space flights, astronauts suffer from lumbar muscle atrophy, reduced range of motion, disc herniations, and disc dehydration, with a high incidence of both acute and chronic pain.