It is unclear how to effectively protect healthcare workers’ mental health during infectious disease epidemics. Targeting the occupational determinants of stress may hold more promise than individual stress management, which has received more focus. Through a systematic review of the 2000–2021 English- and French-language scientific literature, we evaluated the effectiveness of organizational and psychosocial work environment interventions to protect healthcare workers’ mental health in an epidemic/pandemic context. Evidence from medium- and high-quality studies was synthesized using GRADE. Among 1604 unique search results, 41 studies were deemed relevant, yielding 34 low-quality and seven medium-quality studies. The latter reported on promising multi-component prevention programs that combined staffing adjustments, work shift arrangements, enhanced infection prevention and control, recognition of workers’ efforts, psychological and/or logistic support during lockdowns (e.g., accommodation). Our confidence in the effectiveness of reviewed interventions is low to very low, however, owing to methodological limitations. We highlight gaps in the reporting of intervention process and context elements and discuss theory and implementation failure as possible explanations for results. We conclude by urging authors of future studies to include and document detailed risk assessments of the work environment, involve workers in solution design and implementation and consider how this process can be adapted during an emergency.