BACKGROUND: Successful, resilient immunization programs must address complex factors to support vaccine introduction and uptake. We developed an evidence-based tool for use with different populations and vaccines to (i) assess readiness for new and underutilized vaccines, and (ii) assess resilience of existing immunization programs. RESEARCH DESIGN AND METHODS: In Phase 1, we synthesized findings from two published literature reviews to inform a prototype Immunization Program Resilience and Readiness Assessment Tool. In Phase 2, we conducted interviews, surveys, and expert forums with Key Opinion Leaders (KOLs). Phase 2a included 16 global KOLs from 13 countries or regions, refining and renaming the resilience and readiness prototype tool into readiness and resilience global framework. Phase 2b included seven KOLs from the United States (US), refining the prototype tool into a US-specific tool. Phase 3 involved eleven KOLs from four countries who field-tested the global framework for comprehensiveness, relevance, acceptability, and feasibility. RESULTS: We created an evidence-based global framework and context-specific US tool. Field-testing strongly demonstrated the comprehensiveness, relevance, acceptability, and feasibility of use of the global framework. CONCLUSIONS: This framework can support more efficient, equitable, and sustainable immunization programs worldwide. Given the rising nature of vaccine hesitancy, budget constraints, and competing health priorities, there is an increased need for systematic assessment and evidence-based decision-making.