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Alpelisib is currently the only Phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treating endocrine therapy-resistant metastatic breast cancer with a Phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha (PIK3CA)-mutation. Significant side effects of treatment include hepatotoxicity, hyperglycemia, diarrhea, nausea, stomatitis, fatigue, anorexia, and rash. We discuss the case of a 71-year-old woman with PI3K-mutated metastatic breast cancer and diabetes who presented with abdominal pain, nausea, and anorexia. She was started on alpelisib 250 mg daily four days before the hospital presentation. Notable labs at presentation included a glucose of 537 mg/dL and intrinsic renal acute kidney injury (AKI) with a creatinine of 1.6 mg/dL (baseline 1.2–1.3 mg/dL). A Computed Tomography (CT) scan was suggestive of typhlitis/colitis. After excluding other causes of hyperglycemia, she was diagnosed with alpelisib-induced hyperglycemia. Hyperglycemia with alpelisib is often severe and should prompt immediate consultation with endocrinology. Sodium-glucose co-transporter (SGLT) -2 inhibitors have been the most studied. However, concurrent kidney injuries may limit their real-world application. Alpelisib-associated complications subjected our patient to additional imaging, antibiotics, and prolonged hospital stay (6 days). The overall survival is not significantly increased with alpelisib as per the currently available data. More prospective trials will help assess and balance this drug's safety/efficacy profile to achieve better outcomes.