Workplaces are nodes for Severe Acute Respiratory Syndrome Coronavirus 2 transmission and require strategies to protect workers’ health. This article reports on the South African national coronavirus disease 2019 (COVID-19) strategy that sought to ensure workers’ health, protect the economic activity, safeguard livelihoods and support health services. Data from the Occupational Health Surveillance System, Surveillance System of Sentinel Hospital Sites, and government databases (public sector health worker and Compensation Fund data) was supplemented by peer-reviewed articles and grey literature. A multipronged, multi-stakeholder response to occupational health and safety (OHS) policy development, risk management, health surveillance, information, and training was adopted, underpinned by scientific input, through collaboration between government, organized labour, employer bodies, academia, and community partners. This resulted in government-promulgated legislation addressing OHS, sectoral guidelines, and work-related COVID-19 worker's compensation. The OHS Workstream of the National Department of Health provided leadership and technical support for COVID-specific workplace guidelines and practices, surveillance, information, and training, as well as a workplace-based vaccination strategy.