BackgroundA learning health system (LHS) framework provides an opportunity for health system restructuring to provide value-based healthcare. However, there is little evidence showing how to effectively implement a LHS in practice.ObjectiveA mixed-methods review is proposed to identify and synthesize the existing evidence on effective implementation strategies and outcomes of LHS in an international context.MethodsA mixed-methods systematic review will be conducted following methodological guidance from Joanna Briggs Institute (JBI) and PRISMA reporting guidelines. Six databases (CINAHL, Embase, MEDLINE, PAIS, Scopus and Nursing & Allied Health Database) will be searched for terms related to LHS, implementation and evaluation measures. Three reviewers will independently screen the titles, abstracts and full texts of retrieved articles. Studies will be included if they report on the implementation of a LHS in any healthcare setting. Qualitative, quantitative or mixed-methods study designs will be considered for inclusion. No restrictions will be placed on language or date of publication. Grey literature will be considered for inclusion but reviews and protocol papers will be excluded. Data will be extracted from included studies using a standardized extraction form. One reviewer will extract all data and a second will verify. Critical appraisal of all included studies will be conducted by two reviewers. A convergent integration approach to data synthesis will be used, where qualitative and quantitative data will be synthesized separately and then integrated to present overarching findings. Data will be presented in tables and narratively.ConclusionThis review will address a gap in the literature related to implementation of LHS. The findings from this review will provide researchers with a better understanding of how to design and implement LHS interventions. This systematic review was registered in PROSPERO (CRD42022293348).