BACKGROUND: Reliable biomarkers for predicting disease progression in multiple sclerosis (MS) are crucial for advancing precision medicine and optimising treatment strategies. This study evaluates the predictive potential of serum nuclear magnetic resonance (NMR)-based metabolomics, individually and in combination with well-established biomarkers of neuroinflammation (serum glial fibrillary acidic protein, sGFAP) and axonal damage (neurofilament light chain, sNfL), in an extreme-phenotype subset of the Swiss Multiple Sclerosis Cohort (SMSC). METHODS: Serum samples were analysed using NMR-based metabolomics, along with quantification of sNfL and sGFAP. Supervised multivariate analysis was performed to differentiate MS phenotypes and identify future progressors. Multivariable receiver operating characteristic (ROC) analysis evaluated predictive performance, with key metabolite findings validated in an independent Oxford MS cohort. RESULTS: NMR-based metabolomics reliably distinguishes relapsing-remitting MS (RRMS) from secondary-progressive MS (SPMS) and predicts individual transitions. The identified predictive metabolites (lipoproteins, glutamine, alanine, valine, glucose) are also associated with progression independent of relapse activity (PIRA), a clinically relevant marker of sustained disability worsening. This demonstrates that the approach can both stage disease and forecast progression irrespective of stage. ROC analysis shows strong predictive performance (AUC = 0.81, p = 0.001), with external validation confirming robustness. Integration of NMR-metabolomics with sGFAP and sNfL further improves accuracy, yielding AUCs of 0.91 (p < 0.0001) and 0.87 (p = 0.0002), respectively, supported by independent validation. CONCLUSIONS: The integration of metabolic and protein biomarkers enables both accurate staging of RRMS versus SPMS and, critically, early prediction of progression irrespective of stage. This dual capability provides a clinically actionable, serum-based tool that can refine monitoring, improve therapeutic decision-making, and support a shift towards stage-agnostic, progression-focused care in MS.