Peripheral compartment syndrome (PCS) has a complex etiology, with limited treatment options and high patient morbidity. Animal models of PCS have been hampered by differences in cross-species anatomy, physiology, and the relative rarity of the naturally occurring syndrome in animals. In the present study, the combination of saline infusion with intermittent crushing of skeletal muscle consistently caused increased intracompartmental pressure, hypocalemia, and hypercreatinine-phophokinasemia, signs diagnostic of PCS. This method was used to evaluate both the standard PCS treatment, specifically a fasciotomy, and a regenerative medicine approach for treatment-consisting of a fasciotomy with local administration of a biologic scaffold material composed of porcine small intestinal submucosa extracellular matrix (SIS-ECM). The use of this SIS-ECM scaffold in conjunction with a fasciotomy was associated with myogenesis and constructive tissue remodeling in the SIS-ECM-treated animals. At 1 and 3 months after treatment innervated muscle tissue was present at the site of injury. No myogenesis was present in the fasciotomy only treated animals. RAM11+ macrophages, which are associated with constructive tissue remodeling, were present within the injury site in the SIS-ECM-treated animals at 1 month. The present study provides a reproducible animal model with which to study PCS, and shows the potential of a regenerative medicine approach to PCS treatment.