BackgroundPain is highly burdensome, affecting over 30% of long-term care (LTC) residents. Pain significantly reduces residents’ health-related quality of life (HRQoL), limits their ability to perform activities of daily living (ADLs), restricts their social activities, and can lead to hopelessness, depression, and unnecessary healthcare costs. Although pain can generally be prevented or treated, eliminating pain may not always be possible, especially when residents have multiple chronic conditions. Therefore, improving the HRQoL of LTC residents with pain is a priority goal. Understanding factors influencing HRQoL of LTC residents with pain is imperative to designing and evaluating targeted interventions that complement pain management to improve residents’ HRQoL. However, these factors are poorly understood, and we lack syntheses of available research on this topic. This systematic review protocol outlines the methods to identify, synthesize, and evaluate the available evidence on these factors.MethodsThis mixed methods review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We will systematically search Medline, EMBASE, PsycINFO, CINAHL, Scopus, Cochrane Database of Systematic Reviews and ProQuest Dissertation and Thesis Global from database inception. We will include primary studies and systematically conducted reviews without restrictions to language, publication date, and study design. We will also include gray literature (dissertation and reports) and search relevant reviews and reference lists of all included studies. Two reviewers will independently screen articles, conduct quality appraisal, and extract data. We will synthesize results thematically and conduct meta-analyses if statistical pooling is possible. Residents and family/friend caregivers will assist with interpreting the findings.DiscussionThis proposed systematic review will address an important knowledge gap related to the available evidence on factors influencing HRQoL of LTC residents with pain. Findings will be crucial for researchers, LTC administrators, and policy makers in uncovering research needs and in planning, developing, and evaluating strategies in addition to and complementary with pain management to help improve HRQoL among LTC residents with pain.Systematic review registrationPROSPERO CRD42023405425