ABSTRACT Background Wellness initiatives implemented by graduate medical education programs can help mitigate burnout in resident physicians. Objective This systematic review seeks to identify factors that impact the effectiveness of resident wellness interventions and to provide a conceptual framework to guide future interventions. Methods Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 6 electronic databases were searched in November 2019 using variations of the keywords “resident physicians,” “wellness,” and “intervention.” Peer-reviewed full-text English-language articles on controlled studies were considered for inclusion. The quality of the studies was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. Results The initial search disclosed 1196 articles, of which 18 studies enrolling 666 resident physicians met inclusion criteria for qualitative review. Interventions using peer support and individual meditation enhanced well-being. Effective wellness interventions also used educational theory to guide program development, surveyed participants to guide intervention design, incorporated programming into existing didactic curricula, and recruited voluntary participants. The quality of most of the included studies was poor (13 of 18, 72%) and could be improved by using standardized wellness assessments supported by validity evidence. Conclusions This systematic review suggests that future resident wellness initiatives should focus on grounding interventions in educational theory, forging consensus on wellness instruments with validity evidence, and examining the impact of initiatives on patient outcomes. A logic model can provide a framework for designing and implementing effective wellness interventions.