We report the case of a 42-year-old female diagnosed with acute promyelocytic leukemia (APL), who developed differentiation syndrome (DS) on day 14 during induction therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) with sudden-onset dyspnea, abdominal pain, tachycardia, and fever. Her laboratory findings were remarkable for acute kidney injury (AKI), worsening leukocytosis, thrombocytopenia, and lactic acidosis. She was also found to have flash pulmonary edema and a pericardial effusion. Despite immediate dexamethasone and methylprednisolone administration along with cessation of induction therapy, she continued to worsen and suffered a non-shockable cardiac arrest. Return of spontaneous circulation (ROSC) was achieved, but she was in profound shock requiring multiple vasopressors. The patient suffered repeat cardiac arrest later that day and passed away within 24 hours. DS is a potentially life-threatening complication in APL treatment, occurring in about 25% of APL patients and posing significant treatment challenges.