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Background Black and Hispanic individuals experience poorer outcomes related to coronavirus disease (COVID-19), yet have alarmingly lower uptake of the COVID-19 vaccine compared to non-Hispanic White individuals. Objective To explore the perceptions of barriers and facilitators of COVID-19 vaccine acceptance among Black and Hispanic adults in the New York. Methods A qualitative study consisting of one-on-one semistructured interviews with Black and/ or Hispanic adults in New York state was conducted. Participants were recruited from local businesses, community-based social service agencies and Black and Hispanic churches and a college. All data were collected between February and March 2021. Transcripts were analyzed using qualitative thematic analysis. Results A total of 50 individuals (32 [64%] women; mean [SD] age, 42.04 [15.99] years) participated. The majority of participants identified as Black (n = 34, 68%), 9 (18%) identified as Hispanic, 3 (6%) as Black and Hispanic, and 4 (8%) as White and Hispanic. Twenty-two participants (44%) had high-school level education or less. Mistrust emerged as a central barrier to COVID-19 vaccine acceptance. Facilitators of effective COVID-19 vaccine messages include (1) key informants: like me, (2) personalized community outreach, (3) present the facts, and (4) communicate across multiple media platforms. Conclusions This qualitative study found that among Black and Hispanic participants, receipt of reliable vaccine related information, social networks, seeing people like themselves receive the vaccination, and trusted doctors are key drivers of vaccine acceptance.