COVID-19 has disproportionately affected Black, Indigenous, and People of Color (BIPOC) communities, yet rates of COVID-19 vaccination remain low among these groups. A qualitative study was undertaken to better understand the factors contributing to low vaccine acceptance among these communities. Seventeen focus groups were conducted in English and Spanish from 8/21 to 9/22, with representatives from five critical community sectors: (1) public health departments (n = 1); (2) Federally Qualified Health Centers (n = 2); (3) community-based organizations (n = 1); (4) faith-based organizations (n = 2); and (5) BIPOC residents in six high-risk, underserved communities in metropolitan Houston (n = 11), for a total of 79 participants, comprising 22 community partners and 57 community residents. A social-ecological model and anti-racism framework were adopted to guide data analysis using thematic analysis and constant comparison, which yielded five key themes: (1) legacy of structural racism: distrust and threat; (2) media misinformation: mass and social; (3) listening and adapting to community needs; (4) evolving attitudes towards vaccination; and (5) understanding alternative health belief systems. Although structural racism was a key driver of vaccine uptake, a notable finding indicated community residents’ vaccine attitudes can be changed once they are confident of the protective benefits of vaccination. Study recommendations include adopting an explicitly anti-racist lens to: (1) listen to community members’ needs and concerns, acknowledge their justified institutional distrust concerning vaccines, and learn community members’ healthcare priorities to inform initiatives built on local data; (2) address misinformation via culturally informed, consistent messaging tailored to communal concerns and delivered by trusted local leaders through multimodal community forums; (3) take vaccines to where people live through pop-up clinics, churches, and community centers for distribution via trusted community members, with educational campaigns tailored to the needs of distinct communities; (4) establish vaccine equity task forces to continue developing sustainable policies, structures, programs and practices to address the structural issues driving vaccine and health inequities within BIPOC communities; and (5) continue investing in an effective infrastructure for healthcare education and delivery, essential for competently responding to the ongoing healthcare and other emergency crises that impact BIPOC communities to achieve racial justice and health equity in the US. Findings underscore the crucial need to provide culturally tailored health education and vaccination initiatives, focused on cultural humility, bidirectionality, and mutual respect to support vaccine re-evaluation.