Background Socio-economic growth in many low and middle-income countries has resulted in more available, though not equitably accessible, healthcare. Such growth has also increased demands from citizens for their health systems to be more responsive to their needs. This paper shares a protocol for the RESPONSE study which aims to understand, co-produce, implement and evaluate context-sensitive interventions to improve health systems responsiveness to health needs of vulnerable groups in Ghana and Vietnam. Methods We will use a realist mixed-methods theory-driven case study design, combining quantitative (household survey, secondary analysis of facility data) and qualitative (in-depth interviews, focus groups, observations and document and literature review) methods. Data will be analysed retroductively. The study will comprise three Phases. In Phase 1, we will understand actors’ expectations of responsive health systems, identify key priorities for interventions, and using evidence from a realist synthesis we will develop an initial theory and generate a baseline data. In Phase 2, we will co-produce jointly with key actors, the context-sensitive interventions to improve health systems responsiveness. The interventions will seek to improve internal (i.e. intra-system) and external (i.e. people-systems) interactions through participatory workshops. In Phase 3, we will implement and evaluate the interventions by testing and refining our initial theory through comparing the intended design to the interventions’ actual performance. Discussion The study’s key outcomes will be: (1) improved health systems responsiveness, contributing to improved health services and ultimately health outcomes in Ghana and Vietnam and (2) an empirically-grounded and theoretically-informed model of complex contexts-mechanisms-outcomes relations, together with transferable best practices for scalability and generalisability. Decision-makers across different levels will be engaged throughout. Capacity strengthening will be underpinned by in-depth understanding of capacity needs and assets of each partner team, and will aim to strengthen individual, organisational and system level capacities.