<p>Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutic strategies for musculoskeletal regeneration. MSC-EVs, which are enriched with diverse cargos, exert multifaceted biological effects, including the modulation of inflammation, the promotion of angiogenesis, and the regulation of immune responses. They also activate key regenerative signaling pathways, such as the PI3K/Akt, Wnt/β-catenin, TGF-β/Smad, and NF-κB pathways, thereby promoting osteogenesis, chondrogenesis, tenogenesis, and muscle repair to support the repair of bone, cartilage, tendon, and muscle tissues. In addition to their intrinsic activity, advances in bioengineering, including surface modification, cargo engineering, and integration with biomaterial scaffolds, have further increased their therapeutic potential and delivery. Preclinical studies consistently demonstrate efficacy across diverse musculoskeletal tissues, and early clinical trials highlight their translational promise. Nevertheless, clinical application remains constrained by challenges in large-scale production, standardization, and long-term safety evaluation. This review summarizes current knowledge on the mechanisms, therapeutic applications, engineering strategies, delivery systems, and clinical progress of the use of MSC-EVs in musculoskeletal regeneration while highlighting critical obstacles and future directions for their clinical implementation.</p> Graphical Abstract <p></p>