Objective The aim was to recommend an integrated Total Worker Health (TWH) approach which embraces core human factors and ergonomic principles, supporting worker safety, health, and well-being during the COVID-19 pandemic. Background COVID-19 has resulted in unprecedented challenges to workplace safety and health for workers and managers in essential businesses, including healthcare workers, grocery stores, delivery services, warehouses, and distribution centers. Essential workers need protection, accurate information, and a supportive work environment with an unwavering focus on effective infection control. Method The investigators reviewed emerging workplace recommendations for reducing workers’ exposures to the novel coronavirus and the challenges to workers in protecting their health. Using a theoretical framework and guidelines for integrating safety and health management systems into an organization for TWH, the investigators adapted the framework’s key characteristics to meet the specific worker safety and health issues for effective infection control, providing supports for increasing psychological demands while ensuring a safe work environment. Results The recommended approach includes six key characteristics: focusing on working conditions for infection control and supportive environments for increased psychological demands; utilizing participatory approaches involving workers in identifying daily challenges and unique solutions; employing comprehensive and collaborative efforts to increase system efficiencies; committing as leaders to supporting workers through action and communications; adhering to ethical and legal standards; and using data to guide actions and evaluate progress. Conclusion Applying an integrative TWH approach for worker safety, health, and well-being provides a framework to help managers systematically organize and protect themselves, essential workers, and the public during the COVID-19 pandemic. Application By using the systems approach provided by the six implementation characteristics, employers of essential workers can organize their own efforts to improve system performance and worker well-being during these unprecedented times.