Objective To explore the effect of different doses of esketamine on postoperative pain hypersensitivity induced by continuous infusion of remifentanil.Methods Ninety patients undergoing laparoscopic total hysterectomy under general anesthesia were randomly assigned to 1 of 3 groups: high-dose esketamine 0.5mg/kg group (Group H), low-dose esketamine 0.3 mg/kg group (Group L), and a control group (Group C). Group H and Group L were given corresponding doses of esketamine via intravenous injection 5 minutes before anesthesia induction, while Group C was given an equal volume of physiological saline. Pain threshold around the incision area and non-dominant hand medial forearm were measured at 1 day before surgery, 30 minutes, 6 hours, 12 hours, and 24 hours after surgery. We also recorded postoperative incidence of pain hypersensitivity, pain scores, the incidence receiving rescue analgesics, and side effects up to 24 hours after surgery.Results The pain threshold around the skin incision and non-dominant hand medial forearm in Group C was lower than the preoperative baseline value at 30 minutes, 6 hours, and 12 hours after surgery (P<0.05), while there was no statistically significant difference between Group H and Group L compared with the preoperative baseline value (P>005). At 30 minutes, 6 hours, and 12 hours after surgery, the pain threshold in Group H and Group L was higher than that in Group C (P<0.05). There was no statistically significant difference in pain threshold among the three groups of patients 24 hours after surgery (P>0.05). The incidence of pain hypersensitivity in Group H and Group L was lower than that in Group C at 30 minutes, 6 hours, and 12 hours after surgery (P<0.05). There was no statistically significant difference in the incidence of pain hypersensitivity between Group H and Group L. The VAS scores at 6 and 12 hours after surgery in Group H and Group L were lower than those in Group C (P<0.05). The incidence of delirium hallucinations and glandular secretions in Group H was higher than that in Group C and Group L (P<0.05). The rescue analgesia rate in Group C was higher than that in Group H and Group L (P<0.05).Conclusion Intravenous injection of 0.5 mg/kg or 0.3 mg/kg of esketamine during anesthesia induction has a certain preventive effect on pain hypersensitivity of remifentanil, with a lower incidence of adverse reactions for esketamine at 0.3 mg/kg.