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Voriconazole-induced hypoglycemia in non-diabetic patients has rarely been reported. We describe a non-diabetic man, aged 50 years, without hepatic or renal dysfunction who developed severe prolonged hypoglycemia about 28 hours after initiating therapeutic dose of intravenous (IV) voriconazole therapy for invasive pulmonary aspergillosis. He required continuous IV infusion of dextrose solutions to maintain euglycemia. He recovered from hypoglycemia after discontinuation of voriconazole. Higher than normal plasma insulin (30.4 μU/mL) as well as C-peptide (10.04 ng/mL) levels were observed, which reached normal levels after he recovered from hypoglycemia. The temporal association between voriconazole administration and hypoglycemia occurrence led to probability that it was voriconazole-induced. The voriconazole trough level (8.9 μg/mL) checked during the hypoglycemia episode was elevated. The mechanism of hypoglycemia may be strongly attributed to insulinemia resulting from high voriconazole concentration. There is a possibility of genetic polymorphisms in the hepatic cytochrome P450 2C19 isoenzyme in this patient, which altered the voriconazole metabolism, causing high trough levels associated with hypoglycemia. This case suggests that voriconazole has a propensity to alter glucose homeostasis in the absence of liver and kidney dysfunction, and it may induce hypoglycemia without drug over dosage or drug interaction that clinicians should be vigilant about.