Scedosporium prolificans (S. prolificans) is an increasingly prevalent and treatment-resistant opportunistic fungus. The pathogen is known to cause a variety of clinical manifestations ranging from localized cutaneous disease to disseminated systemic infection. Herein we present an otherwise healthy 41-year-old male with biopsy-proven S. prolificans cutaneous infection. The patient experienced drastic clinical improvement on two months of a combination of oral itraconazole and oral minocycline. S. prolificans exhibits resistance to many antifungal agents, thus, single-agent antifungal therapy has a high failure rate and often results in the need for surgical excision or debridement. Recent accounts suggest that minocycline in combination with azole antifungals has a synergistic effect in treating S. prolificans. This case highlights the excellent response to combination oral therapies with minocycline and itraconazole. Prompt and efficacious treatment reduces the risk of destructive or disseminated disease and may avoid the need for surgical intervention.