Objective: Diagnose drivers of disproportionate COVID-19 vaccine hesitancy among educated Ghanaians integrating theoretical frameworks and health systems perspectives. Method: Expanded analysis blending Health Belief, Transtheoretical, Planned Behavior models and Structure-Process-Outcome constructs with scholarly literature, case studies and Public Health Act scrutiny. Results: Multifaceted attitudinal, normative, informational, digital, procedural and policy barriers worsen tertiary-level reluctance trends. Risk/benefit miscalculations coupled with safety misconceptions persist amid unchecked social media falsehoods. Access hurdles, political sensitivities around enforcement and lacking messaging relevance further sustain hesitancy. Conclusions: Overcoming complexity necessitates coordinated communication, convenience/access, regulation and mandate interventions tailored to educate groups’ mindsets and trusted information channels. Recommendations: Context-specific policy reforms addressing risk perceptions, social media governance, registration/delivery pathways and Public Health Act applicability can promote vaccination intentions and behaviors among qualified Ghanaians. Contributions: Granular framework integrating behavioral models with digitization, procedural and policy perspectives to inform tailored reluctance interventions for educated sub-populations. Significance: Advancing vaccine equity and epidemic preparedness in Ghana via evidence-based promotion strategies targeting influential hesitant demographic.