We report a rare and intricate case of nesidioblastosis, marked by hyperinsulinemic hypoglycemia, in a patient with diabetes and chronic kidney disease (CKD). PET-CT imaging and histopathology confirmed the condition, culminating in a comprehensive treatment strategy comprising subtotal pancreatectomy and pharmacotherapy. This case marks the first documented occurrence of nesidioblastosis in a patient with CKD and diabetes. The presence of CKD further complicated the clinical picture, influencing hypoglycemic risk, drug efficacy, insulin clearance, and counter-regulatory mechanisms.