Background: Although theoretical frameworks exist to guide social media interventions, few of them make it explicit how social media is supposed to work to improve the knowledge use by health care providers. This study aimed to synthesize literature to understand how and under what circumstances social media supports knowledge use by health care providers in clinical practice. Methods: We followed the realist review methodology described by Pawson et al. It involved six iterative steps: (1) develop an initial program theory; (2) search for evidence; (3) select and appraise studies; (4) extract data; (5) synthesize data; and (6) draw conclusions. Results: Of the 7,175 citations retrieved, 32 documents were prioritized for synthesis. We identified two causal explanations of how social media could support health care providers' knowledge use, each underpinned by distinct context-mechanism-outcome (CMO) configurations. We defined these causal explanations as: (1) the rationality-driven approach that primarily uses open social media platforms (n = 8 CMOs) such as Twitter, and (2) the relationality-driven approach that primarily uses closed social media platforms (n = 6 CMOs) such as an online community of practice. Key mechanisms of the rationality-driven approach included social media content developers capabilities and capacities, in addition to recipients' access to, perceptions of, engagement with, and intentions to use the messages, and ability to function autonomously within their full scope of practice. However, the relationality-driven approach encompassed platform receptivity, a sense of common goals, belonging, trust and ownership, accessibility to expertise, and the fulfillment of needs as key mechanisms. Conclusion: Social media has the potential to support knowledge use by health care providers. Future research is necessary to refine the two causal explanations and investigate their potential synergistic effects on practice change.