Black men who have sex with men (BMSM) living in the United States (U.S.) South are disproportionately affected by HIV and experience significant disparities in HIV incidence, access to HIV care, and prevention across ages and socio-economic statuses. The aim of this commentary is to critically review current literature on the state of PrEP use among BMSM in the U.S. South, including identifying barriers and facilitators to PrEP use in order to inform intervention development. Extant literature shows that despite the documented benefits of PrEP as an effective HIV-prevention method, its uptake among BMSM is limited across the U.S. South. Common barriers to PrEP uptake included stigma, homophobia, mistrust of healthcare systems, negative attitudes from healthcare providers, access and transportation issues, poverty, and misinformation about PrEP. These barriers are likely to have been further exacerbated by the COVID-19 pandemic. Limited access to PrEP and other HIV-prevention programs, such as HIV testing, post-exposure prophylaxis (PEP), and condoms for BMSM are likely increase HIV incidence in this community. Moreover, the rapid expansion of telehealth services during the COVID-19 period may offer increased opportunity to scale-up PrEP through telehealth interventions, especially if in-person services remain limited due to pandemic precautions. Given the intersectional barriers that limit the access and uptake of PrEP among BMSM, we suggest that tailored programs or interventions that seek to address PrEP disparities among Southern BMSM should adopt intersectional and interdisciplinary approaches to better understand the complex challenges of scaling up PrEP. More studies are needed to investigate the impact of COVID-19 on HIV-prevention services among BMSM and to understand how to co-develop—with the BMSM community and healthcare providers—culturally acceptable interventions to reduce the identified challenges using intersectional and interdisciplinary approaches.