The COVID-19 pandemic has had disproportionate effects on racial and ethnic minority communities, where preexisting clinical and social conditions amplify health and social disparities. Many of these communities report lower vaccine confidence and lower receipt of the COVID-19 vaccine. Understanding factors that influence the multifaceted decision-making process for vaccine uptake is critical for narrowing COVID-19-related disparities. To examine factors that members of multiethnic communities at high risk for COVID-19 infection and morbidity report as contributing to vaccine decision-making. This qualitative study used community-engaged methods to conduct virtual focus groups from November 16, 2020, to January 28, 2021, with Los Angeles County residents. Potential participants were recruited through email, video, and telephone outreach to community partner networks. Focus groups were stratified by self-identified race and ethnicity as well as age. Transcripts were analyzed using reflexive thematic analysis. Themes were categorized by contextual, individual, and vaccine-specific influences using the World Health Organization's Vaccine Hesitancy Matrix categories. A total of 13 focus groups were conducted with 70 participants (50 [71.4%] female) who self-identified as American Indian (n = 17 [24.3%]), Black/African American (n = 17 [24.3%]), Filipino/Filipina (n = 11 [15.7%]), Latino/Latina (n = 15 [21.4%]), or Pacific Islander (n = 10 [14.3%]). A total of 39 participants (55.7%) were residents from high-poverty zip codes, and 34 (48.6%) were essential workers. The resulting themes included policy implications for equitable vaccine distribution: contextual influences (unclear and unreliable information, concern for inequitable access or differential treatment, references to mistrust from unethical research studies, accessibility and accommodation barriers, eligibility uncertainty, and fears of politicization or pharmaceutical industry influence); social and group influences (inadequate exposure to trusted messengers or information, altruistic motivations, medical mistrust, and desire for autonomy); and vaccination-specific influences (need for vaccine evidence by subpopulation, misconceptions on vaccine development, allocation ambiguity, vaccination safety preferences, the importance of perceiving vaccine equity, burden of vaccine scheduling, cost uncertainty, and desire for practitioner recommendation). In this qualitative study, participants reported a number of factors that affected their vaccine decision-making, including concern for inequitable vaccine access. Participants endorsed policy recommendations and strategies to promote vaccine confidence. These results suggest that support of informed deliberation and attainment of vaccine equity will require multifaceted, multilevel policy approaches that improve COVID-19 vaccine knowledge, enhance trust, and address the complex interplay of sociocultural and structural barriers to vaccination.