Background: Despite the availability of COVID-19 vaccines and the proven benefits of vaccinations outweighing the potential risks, hesitancy to accept vaccines and additional doses remains a persistent problem. Therefore, the purpose of the study was to investigate hesitancy, confidence, literacy, and the role of the multi-theory model (MTM) constructs in COVID-19 booster uptake. Methods: This cross-sectional study utilized a 52-item psychometric valid web-based survey conducted during the month of October 2021 to recruit a nationally representative sample of U.S. adults. Univariate, bivariate, and multivariate statistical tests were used to analyze the data. Results: Among the booster hesitant group (n = 209, 41.7%), a significantly larger proportion of respondents were unvaccinated with the primary series (43.5% vs. 11%, p < 0.001), were among 18–44 years age group (51.2% vs. 31.8%, p < 0.001), single or never married (33.0% vs. 24.3%, p = 0.04), had lower education with some high school (6.2% vs. 2.4%, p = 0.03), and identified themselves as Republicans (31.6% vs. 20.5%, p = 0.01). The hesitant group had lower mean scores of vaccine literacy, and vaccine confidence, and had 19% lower odds of behavioral confidence than their non-hesitant counterparts (adjusted odds ratio = 0.81, 95% CI: 0.71–0.92). Conclusions: The findings of this study underscore the need of raising public awareness through effective multi-theory-model-based communication campaigns.