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Perioperative depressive symptoms (PDSs) are common among patients who undergo major surgery and can lead to worse clinical outcomes. Esketamine has been reported to alleviate PDSs in patients undergoing certain types of surgery. However, there is a lack of evidence from large-scale, multisurgery studies to support its therapeutic effects in individuals with preexisting moderate-to-severe PDSs. Thus, we designed this multicenter, randomized, placebo-controlled and double-blinded trial to investigate whether esketamine is associated with greater improvements than the placebo among patients undergoing major surgery. Patients with moderate-to-severe PDSs who underwent major surgery were assessed for eligibility and randomly assigned to receive esketamine or placebo intraoperatively. The primary outcome was the remission rate 3 days after surgery, which was defined as a Montgomery-Åsberg Depression Rating Scale score less than or equal to 10. The secondary outcomes included pain, esketamine-related psychotic symptoms and safety outcomes after surgery. A total of 435 patients were randomized to receive either esketamine (n=218) or placebo (n=217). The remission rate was greater in the esketamine group than in the placebo group at 3 days post-surgery (28.3% vs. 11.3%; OR 3.12 [95% CI, 1.79-5.55]; P <0.001). The rates of acute pain were similar between the two groups. Intraoperative treatment with esketamine resulted in a greater proportion of participants whose depressive symptoms improved, but careful monitoring was necessary because of the possibility of developing dissociative symptoms. The clinical application of esketamine for depressive symptoms should consider its benefits and risks in the future. TRIAL REGISTRATION: Clinicaltrial.gov NCT04425473. LIST OF CHEMICAL COMPOUNDS: Esketamine (PubChem CID: 182137) and Ketamine (PubChem CID: 3821).