Background: We describe the development and testing of a hybrid implementation research (IR) framework to understand the pathways, successes, and challenges in addressing amenable under-5 mortality (U5M) – deaths preventable through health system-delivered evidence-based interventions (EBIs) – in low- and middle-income countries (LMICs). Methods: We reviewed existing IR frameworks to develop a hybrid framework designed to better understand U5M reduction in LMICs from identification of leading causes of amenable U5M, to EBI choice, identification, and testing of strategies, work to achieve sustainability at scale, and key contextual factors. We then conducted a mixed-methods case study of Rwanda using the framework to explore its utility in understanding the steps the country took in EBI-related decision-making and implementation between 2000-2015, key contextual factors which hindered or facilitated success, and to extract actionable knowledge for other countries working to reduce U5M. Results: While relevant frameworks were identified, none individually covered the scope needed to understand Rwanda’s actions and success. Building on these frameworks, we combined and adapted relevant frameworks to capture exploration, planning, implementation, contextual factors in LMICs such as Rwanda, and outcomes beyond effectiveness and coverage. Utilizing our hybrid framework in Rwanda, we studied multiple EBIs and identified a common pathway and cross-cutting strategies and contextual factors that supported the country’s success in reducing U5M through the health system EBIs. Using these findings, we identified transferable lessons for other countries working to accelerate reduction in U5M. Conclusions: We found that a hybrid framework building on and adapting existing frameworks was successful in guiding data collection and interpretation of results, emerging new insights into how and why Rwanda achieved equitable introduction and implementation of health system EBIs that contributed to the decline in U5M, and generated lessons for countries working to drop U5M.