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Introduction Opioid-free anaesthesia (OFA) may reduce opioid-related side effects such as postoperative nausea and vomiting (PONV) and hyperalgesia. This study aims to investigate the effects of balanced OFA on PONV and pain outcomes in patients undergoing video-assisted thoracoscopic surgery (VATS).Methods and analysis This randomised controlled trial will be conducted at the First Affiliated Hospital of Soochow University in Suzhou, China. A total of 120 adults scheduled for VATS lung resection will be randomly assigned with a 1:1 ratio to either an OFA group or a control group, stratified by sex (n=60 in each group). Patients will receive balanced anaesthesia with esketamine, dexmedetomidine and sevoflurane (the OFA group), or sufentanil and sevoflurane (the control group). All patients will receive PONV prophylaxis with intraoperative dexamethasone and ondansetron. Multimodal analgesia consists of intraoperative flurbiprofen axetil, ropivacaine infiltration at the end of surgery and postoperative patient-controlled sufentanil. The primary outcome is the incidence of PONV within 48 hours after surgery. Secondary outcomes are nausea, vomiting, need for antiemetic therapy, pain scores at rest and while coughing, postoperative sufentanil consumption, need for rescue analgesia, length of post-anaesthesia care unit stay, length of postoperative hospital stay, and 30-day and 90-day post-surgical pain and mortality. Safety outcomes are hypotension, bradycardia, hypertension, tachycardia, interventions for haemodynamic events, level of sedation, headache, dizziness, nightmare and hallucination. All analyses will be performed in the modified intention-to-treat population.Ethics and dissemination Ethics approval was obtained from the Ethics Committee of the First Affiliated Hospital of Soochow University (2022-042). All patients will provide written informed consent. The results of this study will be published in a peer-reviewed journal.Trial registration number Chinese Clinical Trial Registry (ChiCTR2200059710).