For national and local leaders to achieve universal health coverage, a new approach or technique to gathering evidence and understanding the contexts that influence the outcome of a study and goes beyond the quantitative results of clinical trials and pilot projects is important. The Doris Duke Charitable Foundation’s African Health Initiative (AHI) was designed to produce this type of knowledge through embedding implementation research into Population Health Implementation and Training (PHIT) partnership projects in five countries (Ghana, Mozambique, Rwanda, Tanzania, and Zambia) with the goal of improving primary health care and population health. In Ghana, this integration of research into implementation has contributed to the successful testing, adaptation and implementation of the Community-based Health Planning and Services (CHPS) model (The Navrongo Pilot Project), with results from the AHI-funded work informing national scale-up of effective practices. Further application of implementation science methods and frameworks to study cross-project lessons also produced the evidence needed by national and local decision makers on how and why different intervention components were successful and where and how local context drove implementation and adaptation. Cross-project research also identified effective approaches across diverse settings for building capacity for data-driven improvement, coaching and mentoring clinicians and researchers, developing locally appropriate interventions to reduce neonatal mortality, and integrating implementation research to inform local implementers and researchers in more effective strategies to strengthen health systems and improve health services and population health. Evidence has already shown the potential for this type of work to accelerate regional learning and spread of successful interventions to achieve targeted health goals more efficiently, better enabling countries to achieve the ambitious, but important, U.N. Sustainable Development Goals.