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Background Long-term care facilities (LTCFs) are high-risk environments for contracting healthcare-associated infections (HCAIs) due to residents’ vulnerability, close living conditions, and frequent interactions between residents and healthcare staff. HCAIs in LTCFs are preventable through infection prevention and control (IPC) clinical best practices. While prior research has demonstrated the clinical effectiveness of these measures in reducing infection rates, less is known about their cost, impact on quality of life, safety, and health outcomes for residents and healthcare professionals. Objective The objective of this systematic review is to assess the impact of IPC measures on costs, quality of life, safety, and health outcomes among residents and healthcare professionals working in LTCFs. Methods This systematic review protocol is registered in the Research Registry ( reviewregistry1949 ) and follows the PRISMA 2020 guidelines. The review is grounded in the Institute for Healthcare Improvement framework of infection control interventions and the World Health Organization Infection Prevention and Control Assessment Framework. Eligible studies will include quantitative designs conducted in LTCFs, published between January 1, 2015, and January 1, 2026. Interventions of interest include IPC-related professional (e.g., infection preventionists, IPC nurses) roles and clinical best practices such as hand hygiene, environmental hygiene, screening, and basic and additional precautions. Outcomes will include measures of quality of life, safety, health, and costs. Economic outcomes will be assessed through cost-evaluation studies. Searches will be conducted in CINAHL, MEDLINE, Web of Science, and Cochrane databases. Data extraction will follow CHEERS guidelines for economic studies and STROBE guidelines for non-economic studies. Study quality will be assessed using the Drummond criteria and ROBINS-I guidelines. Monetary values will be standardized to 2025 Canadian dollars, with discounting and sensitivity analyses applied where appropriate. Expected results This review will synthesize current evidence on the clinical, economic, and quality-related impacts of IPC measures roles in LTCFs, identifying effective and cost-efficient strategies as well as gaps in existing research. Conclusion The findings of this review will provide policymakers, healthcare administrators, and clinicians with evidence-based insights to inform the design and implementation of efficient IPC programs in LTCFs, supporting improved resident outcomes, workforce safety, and sustainable use of healthcare resources. Systematic review registration reviewregistry1949 .