Cell transplantation-based therapy could be an effective way for the treatment of many diseases. Among numerous somatic stem cells isolated and purified, skin-derived precursors (SKPs) are abundant autologous cells, providing a large reservoir of cells for therapeutic transplantation. Previous studies showed that SKPs could be differentiated into neural and mesodermal progeny in vitro. In the present study, we attempted to differentiate SKPs to muscle progenitors in vitro. After treatment with a combination of growth factors, SKPs were differentiated into cells expressing markers of muscle progenitors, including Pax7. Furthermore, some of these cells expressed desmin, TnT, Mstn, and Myog, suggesting their differentiation into the muscular lineage. After single point injection, the differentiation of SKPs from green fluorescent protein positive donors into muscle precursors was also demonstrated in vivo. Additionally, donor SKPs migrated to the niche of muscle progenitors, participated in the regeneration of recipient muscles, and expressed markers of muscle progenitors, including Pax7, M-cadherin, and MyoD. After recovery of donor cells from recipient muscles at 3 weeks postinjection, some of the injected SKPs were converted to myogenic precursors, based on the expression of specific markers (Pax7 and MyoD). Some of these donor cells also expressed muscle makers (desmin, TnT, and Myog). At 20 weeks postinjection, the injected SKPs were localized to recipient muscles without decreases in their population size. In summary, these findings indicated that SKPs could develop into muscle progenitors and differentiated muscle cells in vitro and in vivo, thus providing valuable autologous cells for the treatment of muscle diseases.