Background: Burn patients are a high-risk population for development of opportunistic infections. Patients suffering extensive burns require prolonged hospital stays and often endure multiple infections from multiple drug-resistant organisms (MDRO). In view of the emergence of MDRO, newer less toxic antimicrobial alternatives are sought for better care of these patients. Treatment of severe opportunistic mycoses in burn patients have proved challenging because of the commonly recommended treatment with amphotericin B, a toxic polyene anti-fungal agent. Methods: A novel treatment modality was utilized on one patient with acute renal failure in our regional burn center. Systemic isavuconazonium was used with topical amphotericin B in lieu of the standard therapy of systemic amphotericin B. Results: The patient remained hemodynamically stable and underwent several successful skin grafts to residual open wounds of her head, chest, back, abdomen, and upper extremities. Tissue biopsies during subsequent grafting did not show Mucor growth since therapy initiation. Her renal function recovered completely and renal replacement therapy was discontinued. Conclusions: Dual therapy with systemic isavuconazonium and topical amphotericin B is a viable alternative to treat invasive mucormycosis in burn patients with comorbidities, including acute renal injury (AKI), that prohibit use of amphotericin B systemically.