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Introduction The convergence of digital technologies with point-of-care (POC) diagnostics has paved the way for innovative digital POC diagnostics that combine the convenience and accessibility of POC testing with digital connectivity and data analytics capabilities. Given the burden and mortality from infectious diseases such as malaria in many African countries, rapid diagnosis and treatment are essential for effective disease management. Therefore, this study aims to assess the readiness of African health systems, with a focus on Ghana, to integrate new POC digital diagnostic tools for acute febrile illness by directly learning from stakeholders and intended users.Methods and analysis This study focuses on Ghana’s health system within a broader context of work across six sub-Saharan African countries. It will adopt a mixed-methods approach to assess the readiness of Ghana’s health system to use and integrate new POC digital diagnostic tests for diagnosing acute febrile illness.Data will be collected through a realist evaluation approach, policy analysis, surveys (n≈75), key informant interviews (n≥20), focus group discussions and observations in three regions in Ghana.Stakeholders representing various levels of health system governance, including global, national, regional and district levels, will be purposively selected for qualitative interviews. Analysis will be guided by realist evaluation using context–mechanism–outcome configurations, complemented by a four-by-four implementation framework. Qualitative data will undergo thematic analysis, while quantitative survey data will be analysed using descriptive and inferential statistics. Findings will be triangulated across data sources to refine programme theory and identify context-specific pathways for integration.Ethics and dissemination The study aims to contribute to the design of new POC digital diagnostic tests that are context-appropriate for diagnostic testing in Ghana and similar African contexts. Results will be communicated to relevant communities and stakeholders and disseminated through publications and presentations.PROSPERO registration number CRD420251084372.