Objectives: Due to ongoing societal, racial, and healthcare disparities, Black communities are disproportionately impacted by the COVID-19 pandemic, yet investigations of resulting mental health sequelae for this community remain limited. Utilizing a mixed-methods design, the current study examined the role of COVID-19-related stress, derailment, and resilience, on post-traumatic stress symptoms for Black adults. Methods: A sample of 162 Black adults was assessed to investigate how COVID-19-related stress may be directly and indirectly associated with post-traumatic stress symptoms via increased levels of derailment. We also evaluated the moderating role of resilience. Second, semi-structured interviews with a subsample of Black adults (N = 67) produced rich narratives, which uncovered distinct sources of derailment and resilience for Black Americans. Results: Quantitative findings revealed that COVID-19-related stress was indirectly associated with post-traumatic stress via increased levels of derailment. Further, the association between derailment and post-traumatic stress differed according to one’s level of resilience. The qualitative findings revealed four distinct sources of derailment: 1) unexpected change, 2) social isolation, 3) grief and loss, and 4) uncertainty for the future; and, five distinct sources of resilience: 1) ancestral strength, 2) faith/spirituality, 3) social support, 4) acceptance and self-improvement, and 5) disengagement. Conclusions: Findings from this study center experiences of Black Americans during the COVID-19 pandemic and deepen our understanding of factors that exacerbate risk and promote resilience within the context of a global public health crisis. Implications are discussed for culturally relevant prevention and intervention strategies to better meet the mental health needs of Black Americans.