Black transgender women in the Southeast are at the center of the modern-day HIV crisis in the U.S. This focus group study was aimed at understanding the impacts of the COVID-19 pandemic on the health and well-being of Black transgender women in the U.S. Southeast who are affected by HIV. From April–June 2022, we completed seven focus group interviews with 56 participants. Themes identified across the focus groups show: 1) the challenges that pre-dated COVID-19; 2) the challenges of managing COVID-19 risk; 3) negative consequences for mental health, physical health, and overall well-being; 4) negative trends in coping with pandemic stress; 5) the importance of self-care and social support for managing pandemic stress; and 6) the need for more community-based resources. Findings demonstrate that understanding these social determinants of health is vital to developing support resources in this ongoing health crisis and crises yet to come.