Historical, cultural, and social trauma, along with social determinants of health (SDOH), shape health outcomes, attitudes toward medicine, government, and health behaviors among communities of color in the United States (U.S.). This study explores how trauma and fear influence COVID-19 testing and vaccination among Black/African American, Latinx/Indigenous Latin American, and Native American/Indigenous communities. Leveraging community-based participatory research methods, we conducted 11 virtual focus groups from January to March of 2021 with Black/African American (n = 4), Latinx/Indigenous Latin American (n = 4), and Native American/Indigenous (n = 3) identifying community members in Inland Southern California. Our team employed rapid analytic approaches (e.g., template and matrix analysis) to summarize data and identify themes across focus groups and used theories of intersectionality and trauma to meaningfully interpret study findings. Historical, cultural, and social trauma induce fear and mistrust in public health and medical institutions influencing COVID-19 testing and vaccination decisions in communities of color in Inland Southern California. This work showcases the need for culturally and structurally sensitive community-based health interventions that attend to the historical, cultural, and social traumas unique to racial/ethnic minority populations in the U.S. that underlie fear and mistrust of medical, scientific, and governmental institutions.