Despite increased vaccine availability, hesitancy remains a major barrier to achieving herd immunity in Sub-Saharan Africa. This study used surveys (n = 1,500) and focus group discussions across Kenya, Ghana, and Nigeria to identify sociocultural and informational determinants of vaccine hesitancy among individuals aged 18–35. Results indicate that misinformation on social media (41%) and distrust in government (33%) were leading causes. Educational attainment and healthcare access were protective factors. Findings emphasize the need for community-based communication strategies and culturally tailored interventions to address persistent skepticism.