Objective To investigate the effect of intravenous administration of esketamine on postoperative pain and inflammatory factors of patients with frailty undergoing total hip arthroplasty (THA). Methods A total of 70 patients with frailty who underwent THA under general anesthesia were selected. According to the random number table method, they were divided into two groups (n=35): an esketamine group (group K) and a control group (group C). Group K received intravenous infusion of esketamine (15 μg·kg−1·min−1) 10 min before anesthesia induction until 10 min before surgery, while group C was intravenously pumped with the same volume of normal saline, with other treatment that were the same as those in group K. Both groups were compared for their operation time, anesthesia time, intraoperative blood loss, the consumption of propofol and remifentanil during surgery, recovery time, extubation time, and the time to straight answer. Their resting Visual Analog Scale (VAS) scores 2, 6, 12 h and 24 h after surgery were recorded. Their venous blood samples were collected to measure the levels of C‑reactive protein (CRP), tumor necrosis factor‑α (TNF‑α), and interleukin‑6 (IL‑6) before surgery and 1 h after surgery. The time of first off‑bed activity, Harris hip joint function scores on day 7 after surgery, the consumption of sufentanil within 48 h after surgery, the length of hospitalization stay, and post‑operative complications were also recorded. Results Compared with group C, the consumption of propofol and remifentanil in group K remarkably decreased (P<0.05). There was no statistical difference in operation time, anesthesia time, intraoperative blood loss, recovery time, extubation time and the time to straight answer between the two groups (P>0.05). The resting VAS scores in group K 2, 6 h and 12 h after surgery were lower than those in group C (P<0.05), while no statistical difference was found in resting VAS scores 24 h after surgery (P>0.05). The levels of CRP, TNF‑α and IL⁃6 in the two groups 1 h after surgery were significantly higher than those before surgery (P<0.05). Compared with group C, group K presented remarkable decreases in the levels of CRP, TNF‑α, and IL‑6 1 h after surgery (P<0.05). Compared with group C, group K presented remarkable decreases in the time of first off‑bed activity after surgery and the length of hospitalization stay (P<0.05), increases in Harris hip joint function scores on day 7 after surgery and decreases in the consumption of sufentanil within 48 h after surgery (P<0.05). The incidence of post‑operative complications were lower in group K than those in group C (P<0.05). Conclusions Intravenous administration of esketamine can exert a better postoperative analgesic effect, reduce inflammatory factors and promote early postoperative recovery in patients with frailty after total hip replacement arthroplasty.