Aim: Video-assisted thoracoscopic surgery (VATS) is now a gold standard in treating early-stage empyema, while much debate still exists considering the effectiveness of this approach for late-stage empyema. Most concerns arise from the crowded rib cage, narrow working space, and ability to free trapped lungs quickly, mainly if uniportal VATS is used. However, unlike uniportal VATS lobectomy, there is no consensus about standard steps for uniportal VATS decortication to ensure smooth and effective surgery. We try to offer standard, easy-to-replicate steps for this approach to evaluate the efficacy and safety of the “start away from empyema” approach for uniportal VATS decortication in the management of stage II and III empyema. Methods: A prospective case series study has been conducted on 25 patients. All patients with stage II and III empyema were admitted to the Cardiothoracic Surgery Department between October 2017 and March 2020. VATS procedure was done under general anesthesia by a double-lumen tube for selective ventilation. Demographic data, preoperative diagnosis, intraoperative findings, hospital stay, and complications were recorded. Results: Twenty-five patients were enrolled in this study with a median age of 35 years. The duration of illness ranged between 14 and 60 days, with a median (IQR) of 25 (17) days. In (88%) of the patients, there was a successful outcome defined as a near-complete resolution on Chest X-ray (scoring of 3 or 4) and chest US (scoring of 2 or 3). Only three (12%) patients had a partially successful outcome. All patients with partial success suffered from infection associated with malignant effusion. Conclusion: “Start away from empyema” approach for uniportal VATS decortication in stage II and III empyema could be safe and effective in treating loculated nonmalignant pleural effusion.