Introduction and Importance: Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in children. It often presents with signs and symptoms related to bone marrow failure, but any organ can be affected. The extramedullary symptoms of leukemia are frequent and various. However, leukemia rarely causes serous effusions, especially as the first manifestation. Case Presentation: This case report presents a 17-year-old male who developed cardiac tamponade and pleural effusion that led to severe dyspnea. Examinations and diagnostic procedures revealed underlying pre-B-cell ALL. Clinical Discussion: Pleuropericardial effusion in leukemia is often the result of chemotherapy, infection, and relapse. It is rarely the first manifestation of the disease, especially B-cell ALL. However, analysis of the aspirated fluid may reveal an underlying one, which will help make an early diagnosis and administer the appropriate treatment. Conclusion: When approaching a patient with serous effusion, hematological malignancies should be considered the leading cause.