BACKGROUND: Research on student wellness has highlighted the importance of self-care for medical students; however, scholars have yet to identify the extent to which self-reported engagement in self-care behaviors is associated with attenuation of the negative relationship between stress and quality of life during the initial years of medical education. METHODS: Using a self-report survey designed to measure self-care, perceived stress, and quality of life, we hypothesized that self-care would moderate the relationship between stress and psychological quality of life in medical students, as well as stress and physical quality of life. An online questionnaire was completed by 871 medical students representing 49 allopathic medical colleges throughout the U.S. between December 2015 and March 2016. The survey assessed perceived stress, self-care, quality of life and a variety of demographic variables. Regression analyses were used to assess interaction effects of self-care on the relationships between stress and quality of life. RESULTS: Self-reported engagement in self-care appeared to moderate the relationships between perceived stress and both physical (p < .001) and psychological (p = .002) quality of life. As the level of reported engagement in self-care increased, the strength of the inverse relationship between perceived stress and both physical and psychological quality of life appeared to weaken. CONCLUSIONS: Our findings suggest that self-reported engagement in self-care activities is associated with a decrease in the strength of the relationship between perceived stress and quality of life in medical students. Students who disclose utilizing a multitude of self-care practices throughout their training may also sustain greater resiliency and lower risk for higher levels of distress during medical education.