The simultaneous occurrence of acute coronary syndrome (ACS) and pulmonary embolism (PE) in patients with sickle cell disease (SCD) presents notable diagnostic and management challenges. This case report describes a 25-year-old woman with SCD who, after an uncomplicated laparoscopic cholecystectomy, developed acute retrosternal chest pain, severe dyspnea, and tachycardia. Diagnostic workup included several key methods: thoracic CT angiography was performed, revealing massive bilateral pulmonary embolism and a pulmonary infarct. Echocardiography demonstrated myocardial abnormalities, such as wall motion defects and a mildly reduced ejection fraction. Electrocardiography showed ST-segment depression and T-wave inversions in the anteroseptal leads. To confirm the presence of coronary artery disease, coronary angiography identified significant thrombotic stenosis in the proximal left anterior descending artery. Sickle cell disease was confirmed through a positive sickle cell test, which identified the characteristic hemoglobin S. Despite aggressive treatment, the patient’s condition rapidly deteriorated, leading to death within 24 hours. This case underscores the critical role of a comprehensive diagnostic approach, including specific tests for SCD, in managing severe cardiovascular complications and highlights the need for tailored treatment strategies to improve patient outcomes.