Objectives Growing research indicates that self-compassion is associated with key physical health outcomes in non-clinical adult populations. This systematic review was designed to characterize the mediators linking self-compassion to physical health outcomes, evaluate study quality and theoretical evidence, compare findings to the mental health literature, and provide directions for future research. Methods We searched Embase, Medline, APA PsycInfo, Scopus, AMED, and Web of Science for relevant articles (including the inclusion of formal statistical mediation tests) from 2003 to February 2022. Study quality was assessed with Downs and Black Checklist for Measuring Quality and Mediation Quality Checklist tools. Results We screened 6439 articles for title and abstracts, assessed 101 full texts for eligibility, and included 20 relevant articles. A range of mediators were categorized as testing psychological or behavioral factors. Perceived stress (n = 5), emotion regulation (n = 5), negative affect (n = 3), and coping strategies (n = 3) were the most frequently assessed mediators. In general, self-compassion had a significant indirect effect on physical health via negative affect and perceived stress (in the absence of overlapping affective mediators). Findings for emotion regulation and coping strategies were mixed. Conclusions The mediational evidence linking self-compassion to physical health via psychological and behavioral factors remains underdeveloped and focused on the measures of affect and emotion regulation. Future studies need to broaden the scope of mediators to include other self-regulatory factors indicated by theory (e.g., motivational and physiological indices) and implement designs other than cross-sectional/correlational. Protocol Registration PROSPERO CRD42021241915.