Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used for the treatment of multiple different types of malignancies. Serious grade 3-4 adverse events occur in <10% of the patient population and usually improve with dose reduction. One of the more rarely reported side effects of sunitinib therapy is the development of pyoderma gangrenosum-like ulcerations in the lower extremities. These pyoderma gangrenosum-like ulcerations are difficult to treat and distinguish from similar-appearing dermatological diagnoses. We present a patient with refractory lung carcinoma and a past medical history of squamous cell carcinoma of the lower extremity, who developed a non-healing ulceration at the previous site of her skin cancer while undergoing therapy with sunitinib. At the time of the initial evaluation, the ulceration mimicked recurrent squamous cell carcinoma, posing a diagnostic challenge. Histopathological findings showed epidermal hyperplasia, ulceration, and dense acute inflammation. Despite meticulous wound care and treatment of infection, the ulcer only improved with cessation of sunitinib.