To examine COVID-19 vaccination barriers in the US, this study drew on publicly available county-level data (n = 3130) to investigate the impact of vaccine hesitancy on the relationship between county-level social/structural barriers and vaccine coverage. A hierarchical regression was performed to establish the relationship between the COVID-19 Vaccine Coverage Index (CVAC) and vaccine coverage, assess the moderating effect of vaccine hesitancy on this relationship, and explore the influence of ethno-racial composition on vaccine coverage. A significant, negative relationship (r2 = 0.11, f2 = 0.12) between CVAC and vaccine coverage by county was established (step 1). When vaccine hesitancy was introduced as a moderator (step 2), the model significantly explained additional variance in vaccine coverage (r2 = 0.21, f2 = 0.27). Simple slopes analysis indicated a significant interaction effect, whereby the CVAC–vaccine coverage relationship was stronger in low hesitancy counties as compared with high hesitancy counties. Counties with low social/structural barriers (CVAC) but high hesitancy were projected to have 14% lower vaccine coverage. When county-level ethno-racial composition was introduced (step 3), higher proportions of white residents in a county predicted decreased vaccination rates (p < 0.05). Findings indicate that CVAC should be paired with vaccine hesitancy measures to better predict vaccine uptake. Moreover, counties with higher proportions of white residents led to decreases in vaccine uptake, suggesting that future intervention strategies should also target whites to reach herd immunity. We conclude that public health leaders and practitioners should address both social/structural and psychological barriers to vaccination to maximize vaccine coverage, with a particular focus on vaccine hesitancy in communities with minimal social/structural barriers.