Objectives Latinos are disproportionately vulnerable to severe COVID-19 due to workplace exposure, multigenerational households, and existing health disparities. Rolling out COVID-19 vaccines among vulnerable Latinos is critical to address disparities. This study explores vaccine perceptions of Latino families to inform culturally centered strategies for vaccine dissemination. Method Semistructured telephone interviews with Latino families (22 mothers and 24 youth, 13–18 years old) explored COVID-19 vaccine perceptions including (1) sources of information, (2) trust of vaccine effectiveness and willingness to get vaccinated, and (3) access to the vaccine distribution. We identified thematic patterns using immersion–crystallization. Results We found that (1) 41% expressed optimism and willingness to receive the vaccine coupled with concerns about side effects; (2) 45% expressed hesitancy or would refuse vaccination based on mistrust, myths, fear of being used as “guinea pigs,” and the perceived role of politics in vaccine development; (3) families “digested” information gathered from social media, the news, and radio through intergenerational communication; and (4) participants called for community-led advocacy and “leading by example” to dispel fear and misinformation. Optimistic participants saw the vaccine as a way to protect their families, allowing youth to return to schools and providing safer conditions for frontline essential workers. Conclusions Culturally centered vaccine promotion campaigns may consider the Latino family unit as their target audience by providing information that can be discussed among parents and youth, engaging a range of health providers and advocates that includes traditional practitioners and community health workers, and disseminating information at key venues, such as schools, churches, and supermarkets.