A one-year-old, intact male Maltese was referred with dehydration, anorexia, and marked hyperglycemia. The dog had been managed due to meningoencephalitis of unknown etiology (MUE) for three months. The dog had been treated with long-term prednisolone administration. Diabetic ketoacidosis (DKA) was identified based on the blood chemistry and venous gas analyses, and intensive treatments including insulin administration were initiated. On further examinations, there was no any other disease that contributed to the occurrence of DKA. Insulin resistance resulted from the administration of prednisolone was highly suspected, but the agent could not be tapered due to managing MUE. Following resolution of DKA, the dog was discharged with life-long insulin and prednisolone therapy. Over the next two years, the dog continued to be routinely re-evaluated and was managed with permanent insulin therapy (0.8–1.4 units/kg SC 12 hourly) and medications including prednisolone (0.4–1.1 mg/kg PO 12 hourly). Because MUE severely progressed, the dog was euthanized by owner’s request. Histopathologic examination of pancreas obtained by post-mortem revealed that both endo- and exocrine pancreas was within normal limit. The case described herein showed the risk of ketoacidosis as well as hyperglycemia after long-term prednisolone administration in a dog without pancreatic islet pathology.