Background: Despite the increasing popularity of using social media to disseminate and translate knowledge, there remains a lack of theoretical understanding of how social media can work for healthcare providers’ knowledge use. The purpose of this thesis was to understand how and under what circumstances social media supports healthcare providers’ use of knowledge in clinical practice. Methods: Drawing on the tenets of scientific realism and the context (C) + mechanism (M) = outcome (O) (CMO) heuristic, a three-phase multi-method study was conducted to build a progressive theoretical understanding of how social media supports healthcare providers’ use of knowledge: 1) theory gleaning by a narrative review of five social media initiatives, five theories, and 58 empirical studies; 2) theory refining by a realist review of 32 articles; and 3) theory consolidation by a realist-informed qualitative study with 11 participants. Results: The Social Media for ImpLementing Evidence (SMILE) framework was developed in the theory gleaning phase. In the theory refining phase, two causal explanations were identified: 1) the rationality-driven approach that primarily uses open social media platforms (eight CMOs), and 2) the relationality-driven approach that primarily uses closed social media platforms (six CMOs). In the theory consolidation phase, the program theory developed for open social media platforms from the realist review was refined to ten CMOs, of which four confirmed the original CMOs, four refined the original CMOs, and two were new CMO propositions. The key mechanisms included content developers’ capabilities and capacities, along with healthcare providers’ increased attention; fulfillment of information needs; access to social influence and support; perception of message value and implementability; behaviour capabilities, self-efficacy, intention, and awareness; and ability to exercise professional autonomy. Conclusions: Through a three-phase realist theory development process, a theoretical understanding of how social media supports healthcare providers’ knowledge use in clinical practice was built. Future research is necessary to further develop this framework and investigate the synergistic effects of the rationality and relationality-driven approaches.