Background. Deep wounds with exposed muscle, tendon, and/or bone structures are especially difficult to treat, often requiring a multifaceted approach. Bioactive human skin allograft (BSA) has been proven to be effective in the treatment of deep wounds, but the mechanism of action and clinical use in the real-world setting is not as well known. Objective. The aim of this case series is to study deep wounds treated with BSA to better understand how it is used in real-world patients and discuss its mechanism of action. Materials and Methods. A total of 51 deep wounds of various etiologies and locations were included from 10 sites across the United States. To be included, patients must have failed wound care without BSA for at least 30 days, with more than 50% reduction in size prior to BSA application. Results. The mean wound area was 50.37 cm2 and average wound duration was 3.67 months. The mean time to closure was 15.33 weeks, achieved with an average of 4.24 BSA applications. Many patients received adjunctive therapies either prior to or in combination with BSA. Conclusions. This study demonstrates the effectiveness of BSA in the treatment of deep wounds of various etiologies. The authors provide clinical information on using BSA either alone or in conjunction with other advanced modalities and offer insight into the hypothesized mechanism of action in which these grafts become incorporated. Ultimately, this information can guide best practices in the treatment of full-thickness wounds to improve outcomes.