Abstract:[Objective] To investigate the effect of esketamine (ESK) on fatigue syndrome after total hip arthroplasty (THA) in the elderly. [Methods] A total of 183 elderly patients who were undergoing THA were randomly divided into ESK group (92 cases) and control group (91 cases). The clinical and laboratory results of the two groups were compared. [Results] The ESK group proved significantly lower incidence of intraoperative hypotension than the control group (8.7% vs 19.8%, P=0.039). The occurrence of postoperative fatigue syndrome (POFS) and pain NRS score in both groups were significantly improved over time postoperatively (P<0.05). The ESK group was significantly superior to the control group in terms of incidence of POFS 1 day (13.0% vs 28.6%, P=0.008) and 3 days postoperatively (8.7% vs 19.6%, P=0.026), as well as bed rest time [(7.6±1.3) hours vs (8.2±1.6) hours, P=0.006] and the number of awakening within 7 days after the operation [(82.6±9.2) times vs (90.2±9.3) times, P<0.001]. As for blood test, the interleukin-1β (IL-1β), hypersensitive C-reactive protein (hsCRP), cortisol, serum interleukin-6 (IL-6) were significantly increased in both groups immediately after surgery, 1 and 3 days after surgery compared with those preoperatively (P<0.05). There were no statistical significances in the above test indexes between the two groups before surgery (P>0.05). However, the ESK group had significantly lower levels of the aforesaid test parameters than the control group at all corresponding time points after surgery (P<0.05). [Conclusion] Esketamine reduces the incidence of POFS after THA in the elderly, which may be related to inhibiting inflammatory response, reducing intraoperative hypotension, shortening bed rest time and improving sleep quality.