BACKGROUND: Recent randomized controlled trials have consistently demonstrated the safety and potential efficacy of MSC therapy for heart failure patients. This study delves into mesenchymal stem cells' promising potential, offering a beacon of hope for the future of heart failure treatment with reduced ejection fraction (HFrEF). METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for this systematic review and meta-analysis. We searched four databases and registers for RCTs, including PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other relevant websites. We then selected thirteen RCTs with 1184 participants based on our pre-defined inclusion/exclusion criteria. Two independent assessors extracted the data and performed a quality assessment. The data were then plotted for various outcomes, including death, hospitalization, major adverse cardiac events, pump function parameters, and 6-min walk distance. RESULTS: The safety of MSC-based treatment has been consistently demonstrated with MSCs from autologous (MSCs) and allogeneic (MSCs) sources. This reassuring finding underscores the reliability of MSC-based therapy irrespective of their source. However, MSCs showed a trend toward greater protective benefits. Subgroup analysis revealed no significant differences between MSCs and MSCs in improving LVEF; 0.86% (95% CI - 1.21-2.94%) for MSCs versus 2.17% (- 0.48%; 95% CI - 1.33-5.67%) for MSCs. MSCs significantly reduced end-diastolic volume (LVEDV) by - 2.08 mL (95% CI - 3.52-0.64 mL). Only MSCs significantly improved 6-min walking distance (6-MWD); 31.88 m (95% CI 5.03-58.74 m) for MSCs versus 31.71 m (95% CI - 8.91-71.25 m) for MSCs. The exclusion of studies using adipose-derived cells resulted in even better safety and a significant improvement in LVEF for MSCs treatment. CONCLUSION: Our findings suggest that MSCs are at par with MSCs in improving functional outcomes in heart failure patients. This underscores the need for future investigations in a larger patient cohort, emphasizing the urgency and importance of further research to fully understand the potential of MSCs in treating heart failure.