In this article, we present a case of pyoderma gangrenosum (PG), misdiagnosed initially as a necrotizing infection that significantly worsened due to repeated surgical debridement and aggressive wound care therapy, almost resulting in limb amputation despite antibiotic therapy. The PG lesions improved after pancytopenia were further investigated, and the diagnosis and treatment of an underlying hematologic malignancy was initiated. The diagnosis and management of PG is challenging given the paucity of robust clinical evidence, lack of standard diagnostic criteria, and absence of clinical practice guidelines. It is imperative that clinicians recognize PG as a clinical diagnosis that must be considered in any patient with enlarging, sterile, necrotic lesions that are unresponsive to prolonged and appropriate antibiotics. Early recognition can prevent devastating sequelae such as deep tissue and bone infections associated with a chronic open wound, severe cosmetic morbidity, and potential limb amputation.