Background: Catheter drainage and antibiotics were the standard therapy for parapneumonic effusions and/or empyema. Streptokinase may aid tube drainage if it failed due to fibrinous adhesions. Objective: This study aimed to identify the benefits of streptokinase in treatment of empyema by evaluating its efficacy and safety. Patients and Methods: 30 patients with parapneumonic effusions and/or empyema treated at Al-Azhar University Hospitals between April 2020 and June 2022. The diagnosis was made using a frank pus aspiration from a pleura seen on a chest radiograph (X-ray, ultrasonography, or CT), and it was later confirmed by the results of a bacteriological examination of samples collected. Streptokinase was given 24 hours after insertion of intercostal tube by 250,000 IU diluted in 50–100 ml of ordinary saline and given every 12 hours. The success of the technique was evaluated based on the volume of pleural fluid removed, the treatment's impact on chest radiography, and the incidence of post-injection events. Results: A complete improvement was seen in 21 patients (70%), a moderate effective response in 7 patients (23.3%), and failure was shown in 2 patients (6.7%). Surgical decortication was scheduled in 3 patients who had little to no reaction. Only 6 patients experienced temporary chest discomfort and cough, whereas fever and bleeding were less common. Conclusion: With a lower rate of surgical referral in our study, the therapy of empyema with intrapleural instillation of streptokinase was a safe and effective procedure.