Objective To investigate the effect of intravenous analgesia with esketamine on pain and mood in breast cancer patients. Methods According to the random number table, 60 patients undergoing elective breast cancer surgery were divided into two groups (n=30): an esketamine group and a control group. After surgery, an intravenous analgesia pump was connected. The esketamine group was treated with esketamine in addition to intravenous administration of sufentanil, while the control group underwent intravenous pumping of sufentanil alone, with the same formulation in the rest of treatment. Their Self‑Rating Anxiety Scale (SAS) scores and Self‑Rating Depression Scale (SDS) scores at preoperative 1 day and postoperative 3 days, Visual Analogue Scale (VAS) scores and Ramsay scores at postoperative 1 day and 2 days were recorded. The adverse reactions, use of adjuvant analgesics and satisfaction with analgesia were collected. Results There was no statistical difference in SAS and SDS scores between the two groups at preoperative 1 day (P>0.05). The esketamine group showed lower SAS and SDS scores than the control group at postoperative 3 days (P<0.05). The SAS and SDS scores of the esketamine group at postoperative 3 days decreased compared with those at preoperative 1 day (P<0.05), but the SAS and SDS scores of the control group at postoperative 3 days increased compared with those at preoperative 1 day (P<0.05). There was no statistical difference in Ramsay scores between the two groups at postoperative 1 day and 2 days (P>0.05). Compared with the control group, the esketamine group showed decreases in VAS scores at postoperative 1 day and 2 days (P<0.05). There was no report concerning respiratory depression, and there was no statistical difference in the incidences of dizziness, nausea and vomiting between the two groups (P>0.05). Compared with the control group, the esketamine group presented decreases in postoperative hypotension and the use of adjunctive analgesics (P<0.05). The satisfaction for analgesia in the esketamine group was better than that in the control group (P<0.05). Conclusions Postoperative intravenous analgesia with esketamine can relieve postoperative pain, stabilize patient emotion, reduce the occurrence of adverse reactions, and improve patient satisfaction.