The role of immunization in public health is crucial, offering widespread protection against infectious diseases and underpinning societal well-being. However, achieving optimal vaccination coverage is impeded by vaccine hesitancy, a significant challenge that necessitates comprehensive strategies to understand and mitigate its effects. We propose the integration of Population Health Management principles with Immunization Information Systems (IISs) to address vaccine hesitancy more effectively. Our approach leverages systematic health determinants analysis to identify at-risk populations and tailor interventions, thereby promoting vaccination coverage and public health responses. We call for the development of an enhanced version of the Italian National Vaccination Registry, which aims to facilitate real-time tracking of individuals’ vaccination status while improving data accuracy and interoperability among healthcare systems. This registry is designed to overcome current barriers by ensuring robust data protection, addressing cultural and organizational challenges, and integrating behavioral insights to foster informed public health campaigns. Our proposal aligns with the Italian National Vaccination Prevention Plan 2023–2025 and emphasizes proactive, evidence-based strategies to increase vaccination uptake and contrast the spread of vaccine-preventable diseases. The ultimate goal is to establish a data-driven, ethically sound framework that enhances public health outcomes and addresses the complexities of vaccine hesitancy within the Italian context and beyond.