AIM: To observe the analgesic effect of esketamine in patients with thoracoscopic lobectomy. METHODS: Sixty patients scheduled with thoracoscopic lobectomy were randomly divided into group esketamine (ESK, n=30) and group saline (SAL, n=30). Esketamine in ESK group was given 0.2 mg/kg at induction and 0.12 mg·kg-1·h-1 during surgery. SAL group was given the same volume of saline. VAS scores, expression of inflammatory factors, anxiety and depression scores and related adverse reactions of patients were recorded at departure from PACU (T1), 6 h (T2), 24 h (T3), and 48 h (T4) after surgery. RESULTS: No significant difference was found in demographic data between the two groups. Compared with SAL group, the VAS scores of patients in ESK group at T1, T2 and T4 in resting state and T1 in cough state were significant decreased (P<0.05), and the amount of dezocine use was smaller. The patients in ESK group had significantly lower WBC level, but not IL-6, than SAL group. Difference in the postoperative SpO2 alteration and the incidence of adverse reaction including postoperative nausea, vomiting, dizziness and dissociative symptom had no significance between two groups (P>0.05). CONCLUSION: The administration of esketamine can alleviate the acute postoperative pain in patients that received thoracoscopic lobectomy without increasing side effects, and the underlying mechanism may be related to the alleviation of postoperative leukocytosis.