To inform health communication campaigns for COVID-19 prevention and vaccine promotion among racial and ethnic minorities facing disparities, we conducted formative research by interviewing Hispanic/Latino American (Latino), Black/African American (AA), and American Indian/Alaska Native (AI/AN) participants to explore their challenges during the pandemic, the barriers and facilitators to receiving COVID-19 vaccines, acceptability of using chatbots to deliver COVID-19 and vaccine information, and preferred features and suggestions for culturally tailored prevention messages. Positive perceptions of the COVID-19 vaccine were mainly derived from beliefs that the vaccine can protect oneself and families from getting infected and help stop the pandemic. Negative perceptions of the COVID-19 vaccine were driven by concerns about vaccine safety due to the rapid development process and side effects. Latino participants would like to know more information about the vaccine and evidence of its effectiveness. AA participants identified seeing others, especially government officials, get the vaccine first as a facilitator and low trust in the government and healthcare system as barriers to getting the COVID-19 vaccine. AI/AN participants emphasized the importance of equitable access to the vaccine. Participants preferred messages with the following features: informative and evidence-based messages about COVID-19 and vaccination, encouraging and motivational messages that focused on the hope to end the pandemic and return to normal, prosocial messages, and clear instructions for COVID-19 prevention strategies. Participants also suggested that messages should include different cultural practices, be translated into their native languages, and emphasize care for family members.