Black individuals have been disproportionately affected by the COVID-19 pandemic, likely due in part to historically rooted stressors that lie at the intersection of the COVID-19 pandemic and racism. We used secondary data from The Association of Black Psychologists’ multi-state needs assessment of 2480 Black adults to examine the link between race-related COVID stress (RRCS) and mental health outcomes. We also examined the moderating roles of everyday discrimination, cultural mistrust, Black activism, Black identity, and spirituality/religiosity in these associations. T-tests revealed that several demographic and cultural factors are associated with RRCS endorsement. A series of regression analyses showed that endorsement of RRCS is associated with higher psychological distress and lower well-being, above and beyond several sociodemographic characteristics. While traditional cultural protective factors did not buffer against the effects of RRCS on mental health, cultural mistrust strengthened the positive association between RRCS and psychological distress; nonetheless, the association of cultural mistrusts with psychological distress was only seen in those who endorsed RRCS. We provide recommendations for policymakers, clinicians, and researchers to consider the impact of RRCS when addressing Black mental health and well-being in the age of COVID-19.