Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal damage. Current therapies primarily manage symptoms and slow disease progression but do not achieve remyelination. This systematic review evaluates the efficacy and safety of remyelination-promoting interventions in MS, focusing on clinical trials utilizing outcome measures validated in prior studies as indicators of remyelination. A comprehensive search of PubMed, Embase, Web of Science, and Cochrane Library was conducted in May 2024. Clinical trials assessing interventions with potential remyelinating properties were included. Data extraction followed standardized forms, and study quality was evaluated using ROBINS-I for non-randomized trials and RoB 2.0 for RCTs. Remyelination was assessed using Magnetization Transfer Ratio (MTR), Visual Evoked Potentials (VEPs), Myelin Water Fraction (MWF), Diffusion Tensor Imaging (DTI), and Optical Coherence Tomography (OCT). From 1,615 screened records, 25 studies met the inclusion criteria and were analyzed. Across the 3341 participants, 17 interventions were evaluated. Most studies demonstrated a moderate risk of bias, yet all interventions, except one, were generally safe and well tolerated. Notably, rHIgM22, L-T3, opicinumab, clemastine fumarate, phenonytoin, domperidone, GSK239512, human fetal neural precursor cells (hfNPCs), and low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) exhibited remyelination potential. Additionally, disease-modifying therapies (DMTs) such as Ocrelizumab, Fingolimod, and Natalizumab showed promising effects. Although several interventions demonstrated remyelination potential, limitations such as small sample sizes, short follow-up periods, and lack of standardized clinical endpoints validating remyelination's functional impact, highlight the need for robust clinical trial designs, advanced biomarkers, and combination therapies integrating remyelination, neuroprotection, and immunomodulation to improve MS treatment outcomes.