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Background: Global health agendas have in common the goal of contributing to population health outcome improvement. In theory therefore, whenever possible, country level policy and program agenda setting, formulation and implementation towards their attainment should be synergistic such that efforts towards one agenda promote efforts towards the other agendas. Observation suggests that this is not what happens in practice. Potential synergies are often unrealized and fragmentation is not uncommon. In this paper we present findings from an exploration of how and why synergies and fragmentation occur in country level policy and program agenda setting, formulation and implementation for the global health agendas of Universal Health Coverage (UHC), Health Security (HS) and Health Promotion (HP) in Ghana and Sierra Leone. Our study design was a two country case study. Data collection involved document reviews and Key Informant interviews with national and sub-national level decision makers in both countries between July and December 2019. Additionally, in Ghana a stakeholder workshop in December 2019 was used to validate the draft analysis and conclusions.Results: National and global context, country health systems leadership and structure including resources were drivers of synergies and fragmentation. How global as well as country level actors mobilized power and exercised agency in policy and program agenda setting and implementation processes within country were also important drivers.Conclusions: There is potential in both countries to pull towards synergies and push against fragmentation in agenda setting, formulation and implementation of global health agendas despite the resource and other structural constraints. It however requires political and bureaucratic prioritization of synergies, as well as skilled leadership. It also requires considerable mobilization of country level actor exercise of agency to counter sometimes daunting contextual, systems and structural constraints. [ABSTRACT FROM AUTHOR]