Introduction Despite efforts and repeated calls to improve the organisation and quality of healthcare and services, and in view of the many challenges facing health systems, the results and capacity to adapt and integrate innovations and new knowledge remain suboptimal. Learning health systems (LHS) may be an effective model to accelerate the application of research for real quality improvement in healthcare. However, while recognising the enormous potential of LHS, the literature suggests the model remains more of an aspiration than a reality. Methods and analysis To reach a fine understanding of the implementation of the concepts involved in LHS, we will use a hybrid method which combines concept analyses with systematic review methodology. We will use a two-step analysis, a content analysis to analyse the definitions, uses and attributes of the concept and a systematic review to analyse the concept’s implementation mechanisms. We will search eight databases and grey literature and present a broad synthesis of the available evidence regarding design, implementation and evaluation of LHS in a multilevel perspective. We will follow the latest Preferred Reporting Items for Systematic Review and Meta-Analysis statement for conducting and reporting a systematic review. Two reviewers will independently screen the titles and abstracts against the eligibility criteria followed by full-text screening of potentially relevant articles for final inclusion decision. Conflicts will be resolved with a senior author. We will include published primary studies that use qualitative, quantitative or mixed methods. The assessment of risk of bias will be made using the Mixed-Methods Appraisal Tool. Ethics and dissemination This systematic review is exempt from ethics approval. The results formulated will highlight evidence-based interventions that support the implementation of a national LHS. They will be of particular interest to decision makers, researchers, managers, clinicians and patients allowing finally to implement the promising proposal of LHSs at national scale. PROSPERO registration number CRD42023393565.