Volumetric muscle loss (VML) increases fibrotic tissue leading to deficits in function by interfering with a number of connections including neural, vascular and mechanical that complicate implementing regenerative therapeutics. In this paper, Corona et al. investigate muscle architecture and function after VML in Yorkshire Cross pigs to elucidate whether antifibrotic measures can lessen the accumulation of fibrosis and thus mitigate function deficits. Pigs (n = 10) were Randomly assigned to a sham or ~20% VML injury, then once again randomized to either nintedanib (anti-fibrotic agent) or no treatment for 30 days. In-vivo functional measurements of the anterior compartment, including maximum isometric torque, were made over the course of 30 days using Aurora’s 890A large animal apparatus in addition to tracking compartment volume and muscle stiffness. Further histological and molecular measurements of the muscle tissue were made following euthanizing of the animals. After 4-weeks following the VML injury, nontreated muscles showed a significant (23%) maximal torque deficit in contrast to sham. The affected area of the muscle was significantly stiffer (7-fold) in the VML-nontreated leg compared to the nintedanib treated legs. In addition, there was shown to be roughly 40% greater level of hydroxyproline per mg of muscle than the treated muscles. When taken together, the results show VML causes increased fibrosis and stiffness of the affected tissue. These resultant affects post VML can be lessened following antifibrotic treatment.