Populations at high risk for COVID-19- including Spanish speakers—may face additional barriers to obtaining COVID-19 vaccinations; by understanding their challenges, we can create more equitable vaccine interventions. In this study, we used interviews to identify barriers and enablers to COVID-19 vaccine uptake among participants in the San Francisco Department of Public Health contact tracing program. Data analysis employed Capability, Opportunity, Motivation Behavior model (COM-B) and the Behavior Change Wheel framework as guides to target barriers with interventions and supporting policies. This paper presents data from interviews focused on COVID-19 vaccine uptake that was part of a project to improve COVID-19 preventive behaviors in San Francisco. We completed seventeen interviews between February and May 2021; six (35%) were completed in English and 11 (65%) in Spanish. Barriers to vaccine uptake included an unprepared health system, fear of side effects, limited knowledge, and conflicting information. Behavioral factors influencing vaccine uptake were mainly related to physical opportunity, automatic motivation, and psychological capability. Interventions that could address the most significant number of barriers included education, enablement, and environmental restructuring. Finally, communication and marketing policies that use diverse multi-lingual social media and environmental planning that includes accessible vaccine sites for people with disabilities, literacy barriers, and limited English proficiency could significantly increase vaccination. Public health departments should tailor interventions to high-risk populations by understanding the specific barriers they face. This exploratory study suggests how implementation science can provide frameworks to achieve this.