The super-healing Murphy Roths Large (MRL/MpJ) mouse possesses a superior regenerative capacity for repair of many tissues, which makes it an excellent animal model for studying molecular and cellular mechanisms during tissue regeneration. As the role of muscle progenitor cells (MPCs) in muscle-healing capacity of MRL/MpJ mice has not been previously studied, we investigated the muscle regenerative capacity of MRL/MpJ mice following muscle injury, and the results were compared to results from C57BL/6J (B6) age-matched control mice. Our results show that muscle healing upon cardiotoxin injury was accelerated in MRL/MpJ mice and characterized by reduced necrotic muscle area, reduced macrophage infiltration, and more regenerated myofibers (embryonic myosin heavy chain+/centronucleated fibers) at 3, 5, and 12 days postinjury, when compared to B6 age-matched control mice. These observations were associated with enhanced function of MPCs, including improved cell proliferation, differentiation, and resistance to stress, as well as increased muscle regenerative potential when compared to B6 MPCs. Mass spectrometry of serum proteins revealed higher levels of circulating antioxidants in MRL/MpJ mice when compared to B6 mice. Indeed, we found relatively higher gene expression of superoxide dismutase 1 (Sod1) and catalase (Cat) in MRL/MpJ MPCs. Depletion of Sod1 or Cat by small interfering RNA impaired myogenic potential of MRL/MpJ MPCs, indicating a role for these antioxidants in muscle repair. Taken together, these findings provide evidence that improved function of MPCs and higher levels of circulating antioxidants play important roles in accelerating muscle-healing capacity of MRL/MpJ mice. Stem Cells2019;37:357-367