Hemothorax is a serious complication following thoracic surgery, often resulting from vessel injury or rib fractures, and is typically managed with chest tube drainage. Persistent or loculated hemothorax, referred to as retained hemothorax, may require more invasive interventions, such as thoracotomy. Although the intrapleural administration of tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has shown promise in managing pleural infections, its use for hemothorax remains controversial due to bleeding risks. We present a case of a 74-year-old female who developed a retained hemothorax following a robotic left upper lobectomy for lung cancer. Initial chest tube drainage was insufficient, and her high-risk status rendered her unsuitable for further surgery. After a thorough evaluation and obtaining informed consent, intrapleural tPA and DNase were administered, resulting in significant clinical and radiographic improvement without complications. This case suggests that intrapleural tPA and DNase may be a potential alternative to surgery for managing retained hemothorax. Further studies are needed to establish treatment guidelines.