BACKGROUND: Global Health Initiatives (GHIs) respond to high-impact communicable diseases in resource-poor countries, including health systems support, and are major actors in global health. GHIs could play an important role in countries affected by armed conflict given these countries commonly have weak health systems and a high burden of communicable disease. The aim of this study is to explore the influence of two leading GHIs, the Global Fund and the GAVI Alliance, on the health systems of conflict-affected countries. METHODS: This study used an analytical review approach to identify evidence on the role of the Global Fund and the GAVI Alliance with regards to health systems support to 19 conflict-affected countries. Primary and secondary published and grey literature were used, including country evaluations from the Global Fund and the GAVI Alliance. The WHO heath systems building blocks framework was used for the analysis. RESULTS: There is a limited evidence-base on the influence of GHIs on health systems of conflict-affected countries. The findings suggest that GHIs are increasingly investing in conflict-affected countries which has helped to rapidly scale up health services, strengthen human resources, improve procurement, and develop guidelines and protocols. Negative influences include distorting priorities within the health system, inequitable financing of disease-specific services over other health services, diverting staff away from more essential health care services, inadequate attention to capacity building, burdensome reporting requirements, and limited flexibility and responsiveness to the contextual challenges of conflict-affected countries. CONCLUSIONS: There is some evidence of increasing engagement of the Global Fund and the GAVI Alliance with health systems in conflict-affected countries, but this engagement should be supported by more context-specific policies and approaches.