Purpose <p>The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is a globally utilized disease-specific instrument, yet its psychometric stability across diverse cultural and healthcare landscapes is often assumed. This systematic review aims to quantify the cross-cultural reliability and clinical validity of the MSQOL-54.</p> Methods <p>A systematic search of PubMed and Scopus identified 272 records. Following COSMIN guidelines, ten primary validation studies (<i>N</i> = 1,401) across diverse regions including Europe, the Middle East, Southeast Asia, and Africa were included. Methodological quality was appraised using the COSMIN checklist, and clinical validity was assessed via Pearson correlations between the Physical (PHC) and Mental (MHC) Health Composites and the Expanded Disability Status Scale (EDSS).</p> Results <p>Internal consistency was robust across all versions (α range: 0.78–0.96). The PHC demonstrated a consistent, statistically significant inverse correlation with EDSS (r range: −0.25 to − 0.76). Conversely, the MHC exhibited significant decoupling from neurological disability in 40% of the cohorts. Qualitative synthesis identified two distinct cultural phenomena: a Social Buffer effect in Georgia and Indonesia that preserves mental well-being despite physical decline, and a Reporting Deficit in conservative settings where intimacy-related domains showed high non-response rates due to sociocultural taboos.</p> Conclusion <p>The MSQOL-54 demonstrates robust potential for global application, though its psychometric performance remains contingent on sample size and regional reporting norms. The consistent Physical-Mental Gap underscores that mental well-being is driven by psychosocial resilience rather than neurological status alone. Clinicians and researchers should adopt a dual-composite profiling approach to ensure that the emotional erosion is not obscured by stable physical metrics.</p> Trial Registration: <p>PROSPERO CRD420261282251.</p>