Abstract Purpose of Review To describe how mitigation measures against COVID-19 have impacted HIV and TB research in South Africa. Recent Findings South Africa has the highest number of COVID-19 (34%) cases in Africa, accounting for 43% of all reported COVID-19-related deaths on the continent. The country accounts for 20% of all people living with HIV and ranked third in the world for new TB infections in 2019. Summary While South Africa’s investments in its HIV and TB responses enabled it to pivot rapidly to respond to the emerging COVID-19 epidemic, it negatively impacted the HIV and TB response through temporary suspension of research, diversion of key resources for HIV and TB control, and patient access to health care facilities; the full extent of this has yet to emerge. Success in integrating responses to the colliding epidemics could potentially enhance survival outcomes and ensure gains made to date in HIV and TB are not reversed and we stay on track toward achieving the UN 2030 Sustainable Development Goals.