AIM: To assess esketamine's anti-inflammatory effects during thoracic surgery and its modulation of immune responses. MATERIAL AND METHODS: In a randomized trial, 64 of 73 patients undergoing thoracic surgery were allocated into the Control (not receiving esketamine) or the ES-KTM group (intraoperative esketamine infusion). Blood routine tests were conducted one day before (T0) and one day after the surgery (T3). Plasma levels of tumor necrosis factor-α (TNF-α) and interleukine-10 (IL-10) were analyzed by ELISA, and cell surface markers including CD14, CD16, CD163, CD40, CX3CR1, CD206 were tested by cytometry at the entry to the surgical room (T1) and the skin closure (T2). For the in vitro study, esketamine at 10 μM was employed to treat the lipopolysaccharide (LPS) stimulated macrophage cell line-Raw264.7, and its effects were tested by cytometry and RNA sequencing analysis. KEY FINDINGS: Esketamine application reduces the count of neutrophils and monocytes, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and systemic inflammatory index (SII), and enhances the lymphocyte counting and lymphocyte to monocyte ratio (LMR). Then, esketamine application decreases the plasma TNF-α levels, while maintaining the IL-10 level in comparison with the Control group. Additionally, esketamine reduced the proportion of intermediate monocytes, downregulates the expressions of CD16, CD40 and CX3CR1, while upregulates the CD206 expression. Finally, in the in-vitro study, esketamine inhibits the M1 pro-inflammatory markers in LPS-challenged macrophages, and downregulates multiple immune-related pathways. SIGNIFICANCE: Esketamine mitigates surgery-triggered inflammation by suppressing monocyte/macrophage proinflammatory activity and TNF-α release, offering dual anesthetic and immunomodulatory benefits.