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Introduction Ultrasound-guided serratus anterior plane block (SAPB) is commonly used for postoperative pain management in video-assisted thoracoscopic surgery (VATS). However, the choice of local anaesthetics for SAPB remains controversial. This study aims to compare the efficacy and safety of liposomal bupivacaine versus ropivacaine combined with two local anaesthetic adjuncts (dexamethasone and dexmedetomidine) for postoperative pain relief in VATS patients.Methods and analysis This is a single-centre, double-blinded, randomised controlled trial conducted at the Hangzhou First People’s Hospital Affiliated to Westlake University School of Medicine in Hangzhou, China. A total of 120 adult patients scheduled for VATS will be randomly assigned in a 1:1:1 ratio to one of the following three groups: liposomal bupivacaine (group L), ropivacaine combined with dexamethasone (group D) and ropivacaine combined with dexmedetomidine (group R). The primary outcome is the Numeric Rating Scale pain score at rest at 24, 48 and 72 hours postoperatively. Secondary outcomes include opioid consumption, adverse events, Quality of Recovery-15 scores, patient satisfaction and length of hospital stay.Ethics and dissemination The study was approved by the Ethics Committee of the Hangzhou First People’s Hospital Affiliated to Westlake University School of Medicine (approval number IIT-2024405-01) on 6 November 2024. The protocol was registered in the Chinese Clinical Trial Registry on 9 January 2025. The planned study period is from 1 January 2025 to 31 December 2027, with participant recruitment scheduled from 1 March 2025 to 31 December 2026. Recruitment has not yet started. All participants will provide written informed consent. The results will be disseminated through peer-reviewed journals and academic conferences.Trial registration number ChiCTR2500095609.