Objective <p>Depressive symptoms frequently afflict individuals with Parkinson’s disease (PD). The current study was consequently conducted to determine the efficacy of low-dose intravenous esketamine in managing postoperative depressive symptoms, thereby exploring its potential mechanisms of action in PD patients subjected to non-intracranial surgery.</p> Methods <p>In this randomized, double-blind, placebo-controlled trial, patients were allocated to receive either low-dose esketamine (0.25&#xa0;mg/kg IV bolus at induction followed by 0.125&#xa0;mg/kg/h infusion) or placebo. The primary outcome was the Self-Rating Depression Scale (SDS) score assessed preoperatively and on postoperative days 1, 3, and 7. Secondary outcomes included serum levels of 5-HT, norepinephrine (NE), IL-6, and TNF-α, postoperative pain (VAS), and adverse events.</p> Results <p>A total of 53 patients were enrolled, including 27 patients (mean age:72.93 ± 6.59, 14 males, mean BMI 22.87 ± 2.71) in the control group (C group), and 26 patients (mean age: 70.46 ± 7.85, 11 males, mean BMI 23.32 ± 3.40) in the esketamine group (ES group). Compared to the control group, ES group showed significantly lower SDS scores at all postoperative time points (<i>p</i> &lt; 0.01), with sustained antidepressant effects through day 7. Esketamine selectively increased 5-HT (<i>p</i> = 0.0005) but not NE levels. It also significantly reduced proinflammatory cytokines (IL-6, <i>p</i> &lt; 0.001; TNF-α, <i>p</i> &lt; 0.001) and VAS scores (<i>p</i> &lt; 0.001). The incidence of adverse events was comparable between groups.</p> Conclusion <p>Low-dose intraoperative intravenous esketamine safely mitigates postsurgical depressive symptoms in PD patients following non-intracranial surgery, potentially through synergistic modulation of serotoninergic activity and neuroinflammatory responses.</p> Trial registration <p><a href="http://www.chictr.org.cn">http://www.chictr.org.cn</a>, ChiCTR2500098063, Registration date: 3 March 2025. Retrospectively registratered.</p>