BackgroundConsidering the soaring health-related costs directed toward a growing, aging, and comorbid population, the health sector needs effective data-driven interventions while managing rising care costs. While health interventions using data mining have become more robust and adopted, they often demand high-quality big data. However, growing privacy concerns have hindered large-scale data sharing. In parallel, recently introduced legal instruments require complex implementations, especially when it comes to biomedical data. New privacy-preserving technologies, such as decentralized learning, make it possible to create health models without mobilizing data sets by using distributed computation principles. Several multinational partnerships, including a recent agreement between the United States and the European Union, are adopting these techniques for next-generation data science. While these approaches are promising, there is no clear and robust evidence synthesis of health care applications.ObjectiveThe main aim is to compare the performance among health data models (eg, automated diagnosis and mortality prediction) developed using decentralized learning approaches (eg, federated and blockchain) to those using centralized or local methods. Secondary aims are comparing the privacy compromise and resource use among model architectures.MethodsWe will conduct a systematic review using the first-ever registered research protocol for this topic following a robust search methodology, including several biomedical and computational databases. This work will compare health data models differing in development architecture, grouping them according to their clinical applications. For reporting purposes, a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 flow diagram will be presented. CHARMS (Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies)–based forms will be used for data extraction and to assess the risk of bias, alongside PROBAST (Prediction Model Risk of Bias Assessment Tool). All effect measures in the original studies will be reported.ResultsThe queries and data extractions are expected to start on February 28, 2023, and end by July 31, 2023. The research protocol was registered with PROSPERO, under the number 393126, on February 3, 2023. With this protocol, we detail how we will conduct the systematic review. With that study, we aim to summarize the progress and findings from state-of-the-art decentralized learning models in health care in comparison to their local and centralized counterparts. Results are expected to clarify the consensuses and heterogeneities reported and help guide the research and development of new robust and sustainable applications to address the health data privacy problem, with applicability in real-world settings.ConclusionsWe expect to clearly present the status quo of these privacy-preserving technologies in health care. With this robust synthesis of the currently available scientific evidence, the review will inform health technology assessment and evidence-based decisions, from health professionals, data scientists, and policy makers alike. Importantly, it should also guide the development and application of new tools in service of patients’ privacy and future research.Trial RegistrationPROSPERO 393126; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=393126International Registered Report Identifier (IRRID)PRR1-10.2196/45823