Background: Alpelisib-induced Diabetic ketoacidosis (DKA) has been previously reported in the literature. In this case report, we describe the first case of Alpelisib-induced coexisting of DKA and hyperglycemic hyperosmolar state (HHS). Method: A 59-year-old woman, known to have advanced breast cancer with metastasis to bone, lungs, pleural, presented with a 2-day history of nausea, vomiting, and diffuse abdominal pain. Her breast cancer is ER (+), PR (+), and HER2 (+) with mutation of PIK3CA. She has been treated with hormonal and chemotherapy (Paclitaxel, Epirubicin and cyclophosphamide), but in vain. Further treatment with Alpelisib and fulvestrant was given for the treatment of breast cancer with PIK3CA mutation. Hyperglycemia was developed 7 days after medication. HbA1c level was 6.4%. Sitagliptin was prescribed to treat hyperglycemia. However, persistent hyperglycemia coexisting of DKA and HHS was developed 18 days later. Results: Laboratory data showed high anion gap metabolic acidosis, hyperosmolarity, hyperglycemia, and ketonemia, leading to the diagnosis of Alpelisib-associated HHS coexisting with DKA. Alpelisib was discontinued, and she was treated with intravenous insulin and hydration. After hyperglycemia was resolved, her blood glucose was managed using a regimen combining dapagliflozin and metformin. Discussion: This case highlights the importance of aggressive serum glucose monitoring in patients who taking Alpelisib to prevent hyperglycemic emergencies and notifies Sitagliptin treatment failure. Insulin is required at least during an acute hyperglycemic stage and oral SGLT2 inhibitor combine with metformin might be an effective treatment for Alpelisib-induced hyperglycemia. Future prospective studies are needed.