Isavuconazole is increasingly being used for the treatment of invasive fungal disease (IFD), although real-world pediatric data remain limited. We retrospectively reviewed patients aged ≤18 years who received isavuconazole for fungal infection at two tertiary centers in Chile between 2021 and 2025. Twenty patients were included, with a median age of 13.7 years (IQR, 9.4–15.5); 14 (70%) had an underlying malignancy, and 6 (30%) were allogeneic hematopoietic cell transplant recipients. Isavuconazole was used for treatment in 16 patients and for prophylaxis in 4, predominantly as second-line therapy due to prior antifungal intolerance, inadequate response, drug–drug interactions, or QT prolongation. Fifteen patients had IFD, with Mucorales (n=3) being the most frequently identified pathogens in proven cases and pulmonary involvement predominating in probable IFD. A succesful response at 90 days was achieved in 60% (6/10) of evaluable cases. No breakthrough fungal infections occurred during treatment or prophylaxis. Hepatic enzyme elevations were observed in four patients. Isavuconazole was associated with favorable outcomes and an acceptable safety profile, supporting its use as an alternative antifungal in pediatric patients.