Objective To investigate the impact of esketamine hydrochloride in combination with ultrasound? guided transverse thoracic muscle plane block on stress response and inflammatory levels in patients undergoing cardiac valve replacement under general anesthesia. Methods A total of 120 patients who underwent elective extracorporeal circulation?supported median open heart valve replacement were selected and randomly assigned into four groups using the random number table method： general anesthesia alone （Group G）， general anesthesia with intravenous administration of esketamine （Group E）， general anesthesia with transverse thoracic plane block （Group T）， and esketamine combined with transverse thoracic muscle plane block （Group ET）； each group consisted of 30 cases. Patients in group E and group ET received a continuous infusion of esketamine hydrochloride injection at a rate of 0.2 mg/kg^-1?h^-1 until the completion of the surgical procedure， while patients in group G and group T received an equivalent volume of saline solution until the completion of the surgical procedure. After the induction of general anesthesia， patients in group T and group ET underwent ultrasound?guided bilateral transverse thoracic muscle plane block， while patients in group G and group E did not receive any specific intervention. All four groups received identical protocols for anesthesia induction and maintenance， with self?controlled intravenous analgesic pumps administered to all patients postoperatively. The following time points were recorded： 1 day prior to surgery （T0）， pre?induction of anesthesia （T1）， 1 minute post?tracheal intubation （T2）， 1 minute post?median sternotomy （T3）， 1 minute prior to initiation of cardiopulmonary circulation （T4）， 1 minute after cessation of cardiopulmonary circulation （T5）， 1 minute after completion of surgery （T6）， 1 day post?surgery （T7）， 2 days post?surgery （T8）， and 3 days post?surgery（T9）. Mean Arterial Pressure （MAP） and Heart Rate （HR） were continuously monitored from T1 to T6. The levels of blood glucose and lactate were measured and recorded at T1， T4 to T6. The levels of White Blood Cells （WBC） and C?Reactive Protein （CRP） were assessed at T0， as well as at T7 to T9. The occurrence of postoperative adverse reactions was documented in all four groups. Results （1） Comparison of hemodynamics among the four groups： Compared with group G， there was a significant decrease in MAP and HR at T3 in group T （P < 0.05）. At the T5 time point， MAP was lower in group ET compared to group E， while HR was higher in group ET compared to group T （P < 0.05）. （2） The lactate and blood glucose levels of the four patient groups after extracorporeal circulation transfer were higher than those at the T1 time point （P < 0.05）. Patients in group E had lower lactate values at the T5 time point and lower blood glucose values at the T6 time point compared to group G （P < 0.05）. Additionally， patients in group E exhibited lower lactate and blood glucose values at both the T5 and T6 time points compared to those in group T （P < 0.05）. （3） Compared to T0， the levels of white blood cells （WBC） and C?reactive protein （CRP） were increased in all four groups after surgery （P < 0.05）. At the T7 time point， the WBC levels in group E and group T were significantly lower than those in group G （P < 0.05）. Furthermore， compared to group E and group T， the level of WBC in group ET was significantly lower at T7， while the level of CRP was significantly lower at T8 （P < 0.05）. （4） There were no significant differences observed in postoperative adverse reactions among the four groups （P > 0.05）. Conclusion Combining low?dose esketamine hydrochloride with transverse thoracic muscle plane block under general anesthesia during open heart valve replacement surgery can effectively stabilize the patient's hemodynamics， mitigate perioperative stress response and postoperative inflammation levels， thereby demonstrating significant clinical utility.