Background: Vaccination is likely the most effective approach to protect people from COVID-19. However, partisan differences have persisted for COVID-19 vaccine uptake. Purpose: The purpose of this study is to understand different health beliefs related to COVID-19 vaccine uptake based on Health Belief Model (HBM) constructs among individuals with different political affiliations. Methods: The study used a cross-sectional design and data were collected using an online survey. The survey was developed to assess political affiliation and the HBM constructs operationalized toward COVID-19 vaccination uptake. Results: A total of 1187 individuals completed the survey. Results showed a significant difference between all of the HBM constructs and political affiliation with a small effect size. Compared to republicans and independents, democrats were more likely to take the COVID-19 vaccine. Discussion: Findings from the study suggest that politically affiliated individuals view various constructs of HBM operationalized toward COVID-19 vaccine uptake differently. Translation to Health Education Practice: The risk perception differences based on political affiliations identified in this study can inform community-based intervention to address hesitancy toward COVID-19 vaccination in the United States. These efforts may help the United States reach herd immunity through successful COVID-19 vaccination at the earliest possible date.