Volumetric muscle loss (VML) results in a large void deficient in the requisite materials for regeneration for which there is no definitive clinical standard of care. Autologous minced muscle grafts (MG), which contain the essential components for muscle regeneration, may embody an ideal tissue engineering therapy for VML. The purpose of this study was to determine if orthotopic transplantation of MG acutely after VML in the tibialis anterior muscle of male Lewis rats promotes functional tissue regeneration. Herein we report that over the first 16 weeks post-injury, MG transplantation 1) promotes remarkable regeneration of innervated muscle fibers within the defect area (i.e., de novo muscle fiber regeneration), 2) reduced evidence of chronic injury in the remaining muscle mass as compared to non-repaired muscles following VML (i.e., transplantation attenuated chronically up-regulated TGFß1 gene expression and the presence of centrally located nuclei in 30% of fibers observed in non-repaired muscles), and 3) significantly improves net torque production (i.e., ~55% of the functional deficit in non-repaired muscles was restored). Additionally, voluntary wheel running was shown to reduce the heightened accumulation of extracellular matrix deposition observed within the regenerated tissue of MG-repaired sedentary rats 8 weeks post-injury (Collagen 1% Area: Sedentary vs. Runner, ~41 vs. 30%), which may have been the result of an augmented inflammatory response (i.e., M1 (CCR7) and M2 (CD163) macrophage expression was significantly greater in runner than sedentary MG-repaired muscles two weeks post-injury). These findings support further exploration of autologous minced muscle grafts for the treatment of VML.