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Background Despite the growing evidence of a negative impact of medical school on students’ health and well-being, little is known about protective factors for staying healthy and well during medical education. Therefore, a systematic review of peer-reviewed studies aiming to identify such predictors was conducted. Methods Medline, Embase, and PsychInfo were systematically searched by using preselected MeSH terms to identify English- and German-language peer-reviewed articles (observational studies) examining predictors for medical students’ health and well-being, published between January 2001 and April 2018. Two authors independently selected abstracts reporting predictors for medical students’ health and well-being. Further, two authors extracted information from the identified studies, needed for methodological quality assessment of the studies, as well as for comprehensive description of identified predictors. Results From 5013 hits in the database search, six observational studies met the inclusion criteria and were included in the final analysis. These studies were of heterogeneous design and quality. They featured a wide variety of health and well-being related outcomes and of its predictors. Lower levels of perceived stress, as well as lower levels of neuroticism were found to predict better health-related outcomes. Conclusions Further research, by using harmonized tools for the assessment of outcomes, as well as predictors, is needed to determine what keeps students healthy and well during medical education. Identifying protective factors is an essential prerequisite for the design of evidence-based health-promoting interventions. Electronic supplementary material The online version of this article (10.1186/s12909-019-1532-z) contains supplementary material, which is available to authorized users.