Background <p>Perioperative management of bariatric surgery patients presents multiple challenges for anesthesiologists, particularly optimizing airway and respiratory outcomes. This study investigated the feasibility of esketamine-led opioid-free anesthesia (OFA) for bariatric surgery and assessed postoperative pulmonary complications (PPCs).</p> Methods <p>Patients scheduled for laparoscopic bariatric surgery under combined intravenous–inhalation anesthesia were randomized to receive either esketamine-led OFA (S-Ket group) or opioid-balanced anesthesia with sufentanil and remifentanil (SR-Fen group). The primary outcome was post-surgical PPC incidence, and secondary outcomes were total morphine milligram equivalents (MME) and visual analogue scale (VAS) pain scores at multiple postoperative times.</p> Results <p>Of the 263 patients screened, 100 were enrolled. Incidence of PPCs was significantly lower in the S-Ket group than the SR-Fen group (26.0% vs. 50.0%, risk ratio (RR) 0.52; 95% CI: 030–0.89; <i>P</i> = 0.013), with a notable reduction in hypoxemia (22.0% vs. 42.0%, RR 0.52, 95% CI: 0.28–0.97, <i>P</i> = 0.032). Although VAS scores were comparable between groups at all postoperative time points, opioid consumption within the first 24&#xa0;h post-surgery was significantly reduced in the S-Ket group (<i>P</i> = 0.025). Nystagmus (56.0% vs. 0; <i>P</i> &lt; 0.001) was observed exclusively in the S-Ket group, while there were no other significant group differences in safety outcomes. Post-anesthesia care unit (PACU) stay was longer in the S-Ket group (<i>P</i> = 0.039).</p> Conclusions <p>Esketamine-led OFA for laparoscopic bariatric surgery reduced PPC incidence, particularly hypoxemia. However, reduced opioid consumption did not reach the clinical significance threshold (10 MME), and the regimen may prolong PACU stay.</p> Trial registration <p>This study was registered at the Chinese Clinical Trial Registry ChiCTR2200057066 (Date:27/02/2022).</p>