Simple SummaryMesenchymal stem cells (MSCs) are a promising option for developing new treatments for spinal cord injury (SCI). They can help repair damaged tissue, making them an exciting area of research in regenerative medicine. It is important to study the safety, effectiveness, and best ways to use MSC-based therapies while addressing challenges in bringing these treatments to the clinic. Challenges include finding the best source of MSCs, determining when and how to administer them, and creating standardized methods for handling MSCs. Future research should focus on understanding the long-term effects of MSC treatments, optimizing their delivery, and conducting more clinical trials. Combining MSCs with other treatments might also improve outcomes for patients with spinal cord injuries. By increasing our knowledge of MSCs and their potential, we can offer hope for better recovery and quality of life for those affected by SCI.AbstractSpinal cord injury (SCI) represents a significant medical challenge, often resulting in permanent disability and severely impacting the quality of life for affected individuals. Traditional treatment options remain limited, underscoring the need for novel therapeutic approaches. In recent years, multipotent mesenchymal stem cells (MSCs) have emerged as a promising candidate for SCI treatment due to their multifaceted regenerative capabilities. This comprehensive review synthesizes the current understanding of the molecular mechanisms underlying MSC-mediated tissue repair in SCI. Key mechanisms discussed include neuroprotection through the secretion of growth factors and cytokines, promotion of neuronal regeneration via MSC differentiation into neural cell types, angiogenesis through the release of pro-angiogenic factors, immunomodulation by modulating immune cell activity, axonal regeneration driven by neurotrophic factors, and glial scar reduction via modulation of extracellular matrix components. Additionally, the review examines the various clinical applications of MSCs in SCI treatment, such as direct cell transplantation into the injured spinal cord, tissue engineering using biomaterial scaffolds that support MSC survival and integration, and innovative cell-based therapies like MSC-derived exosomes, which possess regenerative and neuroprotective properties. As the field progresses, it is crucial to address the challenges associated with MSC-based therapies, including determining optimal sources, intervention timing, and delivery methods, as well as developing standardized protocols for MSC isolation, expansion, and characterization. Overcoming these challenges will facilitate the translation of preclinical findings into clinical practice, providing new hope and improved treatment options for individuals living with the devastating consequences of SCI.