Objective: To investigate the effect of esketamine on tourniquet-related lung injury in patients undergoing total knee arthroplasty (TKA) under general anesthesia. Methods: Using stratified random grouping method, 90 patients who underwent elective TKA in our hospital from February to December 2024 were divided into the observation group and the control group, with 45 cases in each group. Both groups received general anesthesia. The observation group was given intravenous injection of esketamine after anesthesia induction, continuous intravenous infusion of esketamine during operation, and postoperative analgesia with sufentanil + esketamine + dexamethasone. The control group was given intravenous injection of normal saline after anesthesia induction, continuous intravenous infusion of sodium chloride injection during operation, and postoperative analgesia with sufentanil + dexamethasone. Blood gas indicators, serum indicators, recovery time, hospital stay, and related pulmonary complications were compared between the two groups. Results: Compared with T0, alveolar-arterial oxygen gradient (PA-aO2) and respiration index (RI) were increased in both groups at T1, T2, and T3. Moreover, the two indicators were lower in the observation group than in the control group (P<0.05). Compared with T0, the levels of endothelin-1 (ET-1) and malondialdehyde (MDA) were increased in both groups at T3, and the levels were lower in the observation group (P<0.05). Recovery time and hospital stay of the observation group were shorter compared with the control group (P<0.05). The total incidence of postoperative pulmonary complications was comparable between the two groups (P>0.05). Conclusion: Esketamine can alleviate tourniquet-related lung injury in patients undergoing TKA under general anesthesia, regulate vascular endothelial function, relieve oxidative stress response, and promote postoperative recovery. However, its impact on postoperative related pulmonary complications needs further study.