The COVID-19 pandemic has disproportionately affected African Americans and has been a significant source of stress for this population due to increased economic hardship and social isolation. This study characterized the associations between COVID-19 vulnerability (e.g., contracting the illness or losing a loved one), pandemic-related stress, and symptoms of poor mental health among African Americans. The study sample included African Americans (N = 304) who responded to an online survey. Symptoms of poor mental health were assessed using the PHQ-4, which assessed symptoms of depression and anxiety. Vulnerability to COVID-19 was measured via self-report in three ways: (1) personal vulnerability, (2) family vulnerability, and (3) community vulnerability (i.e., friends, neighbors, and co-workers). Pandemic-related stress was measured by asking participants to rate how difficult it has been to access essential resources and services, manage finances, and plan or attend social events since March 13, 2020. Data were analyzed using multivariable logistic regression. Results showed that COVID-19 vulnerability was not associated with symptoms of depression or anxiety, but pandemic-related stress was consistently associated with symptoms of poor mental health. Study findings highlight the need to monitor and intervene on pandemic-related stress to prevent further psychological distress within this vulnerable and underserved population.