The COVID-19 pandemic has had a profound impact on emergency department (ED) care in Canada and around the world. To prevent transmission of COVID-19, personal protective equipment (PPE) was required for all ED care providers in contact with suspected cases. With mass vaccination and improvements in several infection prevention components, our hypothesis is that the risks of transmission of COVID-19 will be significantly reduced and that current PPE use will have economic and ecological consequences that exceed its anticipated benefits. Evidence is needed to evaluate PPE use so that recommendations can ensure the clinical, economic, and environmental efficiency (ie, eco-efficiency) of its use. To support the development of recommendations for the eco-efficient use of PPE, our research objectives are to (1) estimate the clinical effectiveness (reduced transmission, hospitalizations, mortality, and work absenteeism) of PPE against COVID-19 for health care workers; (2) estimate the financial cost of using PPE in the ED for the management of suspected or confirmed COVID-19 patients; and (3) estimate the ecological footprint of PPE use against COVID-19 in the ED. We will conduct a mixed method study to evaluate the eco-efficiency of PPE use in the 5 EDs of the CHU de Québec-Université Laval (Québec, Canada). To achieve our goals, the project will include four phases: systematic review of the literature to assess the clinical effectiveness of PPE (objective1; phase 1); cost estimation of PPE use in the ED using a time-driven activity-based costing method (objective2; phase 2); ecological footprint estimation of PPE use using a life cycle assessment approach (objective3; phase 3); and cost-consequence analysis and focus groups (integration of objectives1to3; phase 4). The first 3 phases have started. The results of these phases will be available in 2023. Phase 4 will begin in 2023 and results will be available in 2024. While the benefits of PPE use are likely to diminish as health care workers' immunity increases, it is important to assess its economic and ecological impacts to develop recommendations to guide its eco-efficient use. PROSPERO CRD42022302598; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=302598. DERR1-10.2196/50682.