INTRODUCTION: Effective and sustained postoperative analgesia is essential to enhance recovery after video-assisted thoracoscopic surgery (VATS). Liposomal bupivacaine, a multivesicular formulation enabling extended local anesthetic release, offers a mechanistic advantage over conventional agents. However, prior comparisons with adjuvant-enhanced regimens such as plain bupivacaine plus dexamethasone were confounded by pharmacological and dose inequivalence. This equivalence-dose randomized controlled trial evaluated whether liposomal bupivacaine provides non-inferior analgesia to the standard combination when administered via rhomboid intercostal block (RIB). METHODS: In this double-blind randomized controlled trial, 90 VATS patients were randomly assigned to receive either: a 20-ml premixed solution containing 93 mg of liposomal bupivacaine combined with 25 mg of plain bupivacaine (liposomal bupivacaine group), or a 20-ml admixture of 105 mg of plain bupivacaine and 5 mg of dexamethasone (plain bupivacaine with dexamethasone group). The primary outcome assessed was the area under the curve (AUC) of the 48-h resting pain numeric rating scale (NRS). Secondary outcomes consisted of opioid consumption, dermatomal spread, and Quality of Recovery-15 scores (QoR-15). RESULTS: Liposomal bupivacaine was shown to be non-inferior to plain bupivacaine with dexamethasone, with a 48-h NRS AUC of 105.5 ± 13.6 vs. 113.1 ± 16.3 (mean difference - 7.6; 95% CI - 13.9 to - 1.2, upper limit < non-inferiority margin 3.7). Opioid use and dermatomal spread were comparable within the first 24 h (P > 0.05). There was a notable contrast in sustained dermatome blockade at 48 and 72 h between the two groups (P < 0.001). The liposomal bupivacaine group demonstrated a significantly reduced opioid requirement (P = 0.016) within 24-48 h and superior QoR-15 scores on postoperative day 2 (POD2) (P < 0.001). Safety profiles were comparable, with no between-group differences in postoperative nausea and vomiting or other severe complications (P > 0.05). CONCLUSIONS: Rhomboid intercostal block with liposomal bupivacaine provided similar analgesia to plain bupivacaine with dexamethasone for postoperative pain after VATS. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT06392191). Graphical Abstract available in the Supplementary Materials for this article.