Introduction: Estimating the risk of dental problems in long-duration space missions to the Moon and Mars is critical for avoiding dental emergencies in an environment that does not support proper treatment. Previous risk estimates were constructed based on the experience in short-duration space missions and isolated environments on Earth. However, previous estimates did not account for potential changes in dental structures due to space travel, even though bone loss is a known problem for long-duration spaceflights. The objective of this study was to systematically analyze the changes in hard tissues of the craniofacial complex during spaceflights. Methods: Comprehensive search of Medline, Embase, Scopus, the NASA Technical Report Server, and other sources identified 1,585 potentially relevant studies. After screening, 32 articles that presented quantitative data for skull in humans (6/32) and for calvariae, mandible, and lower incisors in rats (20/32) and mice (6/32) were selected. Results: Skull bone mineral density showed a significant increase in spacefaring humans. In spacefaring rodents, calvariae bone volume to tissue volume (BV/TV) demonstrated a trend toward increasing that did not reach statistical significance, while in mandibles, there was a significant decrease in BV/TV. Dentin thickness and incisor volume of rodent incisors were not significantly different between spaceflight and ground controls. Discussion: Our study demonstrates significant knowledge gaps regarding many structures of the craniofacial complex such as the maxilla, molar, premolar, and canine teeth, as well as small sample sizes for the studies of mandible and incisors. Understanding the effects of microgravity on craniofacial structures is important for estimating risks during long-duration spaceflight and for formulating proper protocols to prevent dental emergencies. Knowledge Transfer Statement: Avoiding dental emergencies in long-duration spaceflights is critical since this environment does not support proper treatment. Prior risk estimates did not account for changes in dental structures due to space travel. We reviewed and synthesized the literature for changes in craniofacial complex associated with spaceflight. The results of our study will help clinicians and scientists to better prepare to mitigate potential oral health issues in space travelers on long-duration missions.