Purpose: Anesthesia for metabolic–bariatric surgery is challenging due to the increased risk of opioid-related adverse events. The purpose of the investigation was to assess the feasibility and efficacy of multimodal opioid-free general anesthesia with transversus abdominis plane (TAP) block for laparoscopic sleeve gastrectomy in contrast with conventional opioid-based general anesthesia. Patients and Methods: Eighty patients who underwent laparoscopic sleeve gastrectomy and eventually 71 patients included in the analysis. They were randomly divided into an opioid-based anesthesia group (control group) with sufentanil or opioid-free anesthesia (OFA) group. Esketamine, dexmedetomidine, and TAP were as part of the OFA. Sevoflurane, dexamethasone, and muscle relaxants were administered intraoperatively to all patients. The primary outcome was antiemetic rescue within 24 hours after surgery. The secondary outcomes included pain scores, analgesic needs, extubation time, complications, the hemodynamic changes, and duration of hospital stay. Results: In contrast with the control group, the need for antiemetic rescue was significantly reduced (p= 0.035). Furthermore, the visual Analog Scale (VAS) for postoperative pain was considerably lower in the OFA group (p < 0.01) than it was in the control group. There was no significant difference in the need for analgesic rescue in both groups (p= 0.155). Extubation time and post-anesthesia care unit (PACU) stay duration were equal between the two groups (p =0.328 and p =0.54). At the end of the surgery and after extubation, hemodynamic changes was more pronounced in the OFA group (p =0.027) than the control group. The length of the hospital stay was significantly shorter compared with the control group (p =0.002). Conclusion: OFA with TAP results in a significant decrease in the need for antiemetic rescue, a lower level of pain after the surgery, and a shorter hospital stay in contrast with anesthesia based on opioids.