BACKGROUND: The increasing use of targeted oral anticancer agents (OAAs) has transformed cancer treatment, yet patient adherence in real-world settings remains suboptimal. This protocol outlines a multi-phasic, hybrid effectiveness-implementation trial designed to develop, implement, and evaluate a risk-adapted, longitudinal medication adherence intervention for patients prescribed OAAs. METHODS: Drawing on social cognitive theory, intervention mapping, and implementation science, the study aims to address barriers at cognitive, behavioral, and environmental levels that impact adherence. Phase 1 identifies implementation barriers and refines strategies, informed by expert input and semi-structured interviews. Phase 2 incorporates patient-centered feedback to tailor a theory-driven intervention targeting adherence barriers. In Phase 3, the intervention is piloted across diverse clinical settings to assess its effectiveness and implementation feasibility. CONCLUSION: This trial aims to deliver a scalable and sustainable model for adherence support, with broad implications for improving patient outcomes and integrating adherence monitoring in routine cancer care.