Background <p>The Quintuple Aim has emerged as an expanded framework for assessing health system performance by integrating patient experience, population health, cost and efficiency, workforce well-being, and equity. While increasingly referenced in policy and academic discourse, it remains unclear how this framework has been empirically operationalized in health services research. This systematic review aims to synthesize empirical applications of the Quintuple Aim, examining their conceptual foundations, methodological approaches, contexts of implementation, and reported outcomes.</p> Methods <p>A systematic review was conducted following PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD420251083698). Searches were performed in PubMed/MEDLINE, Embase, LILACS, and multiple grey literature sources for studies published between January 2020 and July 2025. Eligible studies included empirical applications addressing all five dimensions of the Quintuple Aim across any health system context. Study selection, data extraction, and quality appraisal using the Mixed Methods Appraisal Tool (MMAT) were conducted independently by at least two reviewers. Findings were synthesized narratively following SWiM recommendations.</p> Results <p>Six empirical studies met the inclusion criteria. Most applications built incrementally on prior Triple or Quadruple Aim frameworks rather than representing a distinct evaluative paradigm. Considerable heterogeneity was observed in study designs, outcome definitions, and measurement strategies. Patient experience, workforce well-being, and process-level outcomes were most consistently assessed, while equity and population health outcomes were variably defined and often addressed indirectly. Few studies explicitly examined trade-offs between Quintuple Aim dimensions, particularly between efficiency, equity, and workforce well-being.</p> Conclusions <p>Empirical applications of the Quintuple Aim remain limited and methodologically fragmented. The framework is most effectively understood as an integrative lens for examining interactions and tensions across health system goals rather than as a prescriptive checklist. Advancing its empirical use will require clearer operational definitions, equity-oriented measurement strategies, longitudinal and mixed-methods designs, and greater contextual sensitivity. Strengthening the evidence base is essential to support health system transformation efforts that are efficient, patient-centered, equitable, and sustainable.</p> Clinical trial number <p>Not apply. </p>