In an increasingly volatile, uncertain, complex, and ambiguous (VUCA) environment, the demand for agile, resilient, and cost-effective digital delivery has intensified across sectors. This paper explores the evolving discipline of agile portfolio prioritization as a strategic enabler for enhancing system resilience and optimizing resource allocation in digital transformation initiatives. Beginning with a review of theoretical foundations and the shift from traditional to agile paradigms, the study highlights core values such as responsiveness, stakeholder alignment, and continuous delivery. It integrates resilience theory—emphasizing adaptability, robustness, and redundancy—with frameworks for cost-efficiency, including lean thinking and value stream mapping. Through the lens of dynamic prioritization criteria and tools such as WSJF, MoSCoW, and cost-of-delay, the paper demonstrates how organizations maintain strategic focus and service continuity in times of crisis. Case studies from enterprise, public sector, and cross-industry contexts illustrate practical applications and reveal both common pitfalls and best practices. The discussion concludes with implications for leaders and policymakers, advocating for AI-assisted prioritization and ESG-aligned portfolio models as key directions for future research and operational advancement.