Objective This study aims to explore the impact of esketamine combined with hip pericapsular nerve block on perioperative stress reactions， immune function， cognitive function， and postoperative analgesic efficacy in elderly patients undergoing total hip replacement. Methods From February 2022 to February 2025， 110 elderly patients who received total hip arthroplasty in the hospital were enrolled as the research participants. They were allocated into a control group and an observation group by means of a random number table， with 55 cases in each group.? All patients received total hip arthroplasty. Patients in the control group were given 20 mL of ropivacaine combined with pericapsular nerve block anesthesia of the hip joint， while those in the observation group were given esketamine combined with pericapsular nerve block anesthesia of the hip joint. The blood pressure， heart rate （HR）， oxygen saturation （SpO?）， and respiratory rate （RR） of the two groups were compared at admission （T₁）， immediately after anesthesia （T₂）， skin incision （T₃）， 30 minutes after surgery initiation （T₄）， incision suture （T₅）， and immediately after surgery completion （T₆）. Both groups underwent detection， assessment， and comparison of immune function indices， serum stress markers， and cognitive function scores before the operation and 3 days post-surgery. The Visual Analogue Scale （VAS） pain scores at 3， 6， and 9 hours after surgery were contrasted between the two groups. Additionally， statistical analysis was performed on the incidence of adverse reactions in both groups. Results The HR， mean arterial pressure （MAP）， SpO?， RR， and bispectral index （BIS） of the two groups from T1 to T6 were compared using repeated measures analysis of variance. The results showed that： （1）There were statistically significant differences in HR， MAP， SpO?， and BIS at different time points （F = 118.378， 70.002， 44.910， 242.439， all P < 0.001）. （2）There were statistically significant differences in HR， MAP， SpO?， and BIS between the observation group and the control group （F = 206.643， 195.586， 93.077， 3.953， P < 0.001， P < 0.001， P < 0.001， P = 0.049）. （3）There were statistically significant differences in the changing trends of HR， MAP， SpO?， RR， and BIS between the two groups （F = 18.583， 14.158， 23.350， 4.883， 6.698， all P < 0.001）. At 3 days after surgery， the levels of CD4? and CD4?/CD8? in the observation group were lower than those in the control group （P < 0.05）. The levels of malondialdehyde （MDA）， superoxide dismutase （SOD）， and cortisol in the observation group were lower than those in the control group during surgery and immediately after surgery （P < 0.05）. The Montreal Cognitive Assessment （MoCA） scores and Mini-Mental State Examination （MMSE） scores of both groups decreased 3 days after surgery， and those in the observation group were higher than those in the control group （P < 0.05）. The VAS pain scores of the observation group at 3， 6， 9 and 12 hours after surgery were lower than those of the control group. The incidence of adverse reactions in the observation group was lower than that in the control group （12.73% vs. 29.09%， P < 0.05）. Conclusion Esketamine combined with pericapsular nerve block of the hip joint can significantly inhibit the perioperative stress response in elderly patients undergoing total hip arthroplasty， optimize the postoperative analgesic effect， and reduce the incidence of adverse reactions.