Objective <p>This systematic literature review (SLR) was conducted to explore the role of serum neurofilament light chain (sNfL) as a biomarker in multiple sclerosis (MS) disease management.</p> Methods <p>The review was conducted in accordance with the recommendation laid by the Cochrane Handbook for Systematic Reviews. A comprehensive literature search was performed in key biomedical databases (EMBASE^®, MEDLINE^®, MEDLINE^®-In-Process, and all Evidence-Based Medicine [EBM] Reviews databases) to retrieve studies reporting the association between sNfL and disease activity in patients with MS. Additional evidence was also identified through hand searching of key conference proceedings and gray literature.</p> Results <p>Following review of 1831 records, 75 studies from 180 publications were included in the review. The studies included in the SLR consistently demonstrated an association between higher sNfL levels and an increased risk of future relapses within 2&#xa0;years and MS disease progression. Higher levels of sNfL were also linked to an increased likelihood of experiencing gadolinium-enhancing T1 and T2 lesions. Patients with lower sNfL levels had a higher likelihood of achieving no evidence of disease activity status. Furthermore, an inverse correlation was observed between sNfL levels and cognitive impairment as assessed via the Symbol Digit Modalities Test performance and Timed 25-Foot Walk scores.</p> Conclusion <p>This SLR demonstrates the significance of sNfL as a sensitive biomarker for monitoring MS progression. Convenient and reliable sNfL measurement could benefit routine clinical practice, providing clinicians with a simple and effective tool to monitor disease and treatment response.</p>