AbstractVolumetric muscle loss (VML) is associated with persistent functional impairment due to a lack of de novo muscle regeneration. As mechanisms driving the lack of regeneration continue to be established, adjunctive pharmaceuticals to address the pathophysiology of the remaining muscle may offer partial remediation. Studies were designed to evaluate the tolerance and efficacy of two FDA‐approved pharmaceutical modalities to address the pathophysiology of the remaining muscle tissue after VML injury: (1) nintedanib (an anti‐fibrotic) and (2) combined formoterol and leucine (myogenic promoters). Tolerance was first established by testing low‐ and high‐dosage effects on uninjured skeletal muscle mass and myofiber cross‐sectional area in adult male C57BL/6J mice. Next, tolerated doses of the two pharmaceutical modalities were tested in VML‐injured adult male C57BL/6J mice after an 8‐week treatment period for their ability to modulate muscle strength and whole‐body metabolism. The most salient findings indicate that formoterol plus leucine mitigated the loss in muscle mass, myofiber number, whole‐body lipid oxidation, and muscle strength, and resulted in a higher whole‐body metabolic rate (p≤ 0.016); nintedanib did not exacerbate or correct aspects of the muscle pathophysiology after VML. This supports ongoing optimization efforts, including scale‐up evaluations of formoterol treatment in large animal models of VML.