Volumetric muscle loss (VML) injury is a type of orthopedic trauma characterized by a severe loss of tissue, ultimately leading to long-lasting functional deficits. Patients suffering from VML often suffer from a poor range of motion, limb stiffness, and decreased strength. Despite these debilitating effects, there are no standard practices in the clinic to address soft tissue damage. This therapeutic desert means that patients are more likely to suffer decreasing mobility, which, combined with lean muscle mass loss, contributes to disability and the development of whole-body metabolic disease. The failure to create a standard clinical treatment to improve muscle function following VML partly stems from the lack of understanding of disease progression and how this affects contractility and metabolism. I designed and executed three studies with the purpose of providing an in-depth analysis of metabolic dysfunction following VML injury that could help dictate the development of future therapies by taking the needs of the recovering muscle into consideration. Study 1 evaluated the changes in metabolic flexibility and substrate preference in the early stages following VML injury. Injured muscle presented suppressed response to carbohydrate-driven metabolism compared to healthy muscle, though there was less variability in lipid-driven metabolism. Study 2 tested the efficacy of four FDA-approved medications with history of use in skeletal muscle disease models on rescuing contractile and oxidative function following VML. From these experiments, treatment with formoterol resulted in the partial rescue of muscle function over non-treatment. Study 3 combined the pharmacological adjuvant formoterol with rehabilitation and regenerative method approaches to improve the drug’s effect. The combination of formoterol with rest and voluntary exercise offered an improvement in the contractile and metabolic function of VML-injured tissue. Overall, the work included herein adds to the growing library of knowledge regarding VML injury pathophysiology and offers therapeutic targets and candidates for further development for in-clinic use.