The assurance of safety and effectiveness is a significant focal point in all therapeutic approaches. Although mesenchymal stem cells (MSCs) have been identified as a potential novel therapeutic strategy for multiple sclerosis (MS), existing evidence regarding the effectiveness and safety of this strategy remains inconclusive. Thus, the primary aim of this systematic review and meta-analysis (SRMA) was to comprehensively assess the effectiveness and safety of MSC therapy in individuals diagnosed with MS. A comprehensive search was conducted using appropriate keywords in the PubMed, Scopus, Cochrane, ScienceDirect, and Google Scholar databases to determine the eligible studies. The change in the expanded disability status scale (EDSS) score from baseline to follow-up was used to assess MSC efficacy. The effectiveness of the therapy was assessed using a random-effects model, which calculated the combined prevalence and 95% confidence intervals (CIs) for MS patients who experienced improvement, stability, or worsening of their condition. The protocol was registered in PROSPERO (CRD42020209671). The findings indicate that 40.4% (95% CI: 30.6-50.2) of MS patients exhibited improvements following MSC therapy, 32.8% (95% CI: 25.5-40.1) remained stable, and 18.1% (95% CI: 12.0-24.2) experienced a worsening of their condition. Although no major complications were observed, headaches 57.6 [37.9-77.3] and fever 53.1 [20.7-85.4] were commonly reported as minor adverse events. All of the results reported in this meta-analysis are consistent and credible according to the sensitivity analyses. Regardless of different individual studies, our meta-analysis provides a comprehensive overview showing the potential of MSC therapy as a possible effective treatment strategy for patients with MS.