INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disorder with an unpredictable outcome at the time of diagnosis. The measurement of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) has introduced new biomarkers for assessing MS disease activity and progression. However, there is a need for additional diagnostic and prognostic tools. In this study, we investigated the predictive abilities of metabolomics, gut microbiota, as well as clinical and lifestyle factors for MS outcome parameters. OBJECTIVES: The aim of this study was to assess the predictive capacity of plasma metabolites, gut microbiota, and clinical/lifestyle factors on MS outcome measures including MS-related fatigue, MS disability, and sNfL and sGFAP concentrations. METHODS: A prospective cohort study was conducted with 54 individuals with MS. Anthropometric, biological, and lifestyle parameters were collected. The least absolute shrinkage and selection operator (LASSO) algorithm with ten-fold cross-validation was used to identify predictors of MS disease outcome parameters based on plasma metabolomics, microbiota sequencing, and clinical and lifestyle measurements obtained from questionnaires and anthropometric measurements. RESULTS: Circulating metabolites were found to be superior predictors for sNfL and sGFAP concentrations, while clinical and lifestyle data were associated with EDSS scores. Both plasma metabolites and clinical data significantly predicted MS-related fatigue. Combining multiple multi-omics data did not consistently improve predictive performance. CONCLUSIONS: This study highlights the value of plasma metabolites as predictors of sNfL, sGFAP, and fatigue in MS. Our findings suggest that prioritizing metabolomics over other methods can lead to more accurate predictions of MS disease outcomes.