Objective To evaluate the effectiveness and safety of esketamine for postoperative analgesia in patients undergoing laparoscopic radical colon cancer surgery under general anesthesia. Methods A total of 89 patients who underwent laparoscopic radical colon cancer surgery under general anesthesia in Affiliated Cancer Hospital of Zhengzhou University from February 2022 to July 2022 were selected. According to the random number table method, the patients were divided into three groups: a control group (group C, n=30), a low‑dose esketamine group (group K1, n=29), and a high‑dose esketamine group (group K2, n=30). Their anesthesia induction and maintenance regimens were determined by corresponding anesthesiologists, and the used analgesics were limited to sufentanil and remifentanil. According to the grouping, postoperative patient‑controlled intravenous analgesia pumps were used: sufentanil 1.5 μg/kg+tropisetron 5 mg in group C; sufentanil 1 μg/kg+esketamine 1 mg/kg+tropisetron 5 mg in group K1; and sufentanil 1 μg/kg+esketamine 2 mg/kg+tropisetron 5 mg in group K2. Their Visual Analogue Scale (VAS) score, Ramsay score, the Mini‑Mental State Examination (MMSE) score, the Self‑Rating Depression Scale (SDS) score, the number of analgesic pump compressions within 48 h after surgery, and the incidences of adverse reactions (nausea, vomiting, itching, and urinary retention) were recorded. Results Compared with group C, group K1 showed increases in VAS score at postoperative 48 h (P<0.05), and the number of analgesic pump compressions within 48 h after surgery (P<0.05), while SDS scores at postoperative 48 h decreased in groups K1 and K2 (all P<0.05). Compared with group K1, group K2 presented reduced VAS scores at postoperative 48 h (P<0.05), with a decreased number of analgesic pump compressions within 48 h after surgery (P<0.05). There was no statistical difference in Ramsay score and MMSE score at postoperative 48 h among the three groups (all P>0.05). The incidence of nausea within 48 h after surgery in groups K1 and K2 was lower than that in group C (all P<0.05). There was no statistical difference in the incidence of other adverse reactions (all P>0.05). Conclusion It is safe and effective to use esketamine tropisetron 2 mg/kg+sufentanil 1 μg/kg for postoperative analgesia in patients undergoing laparoscopic radical colon cancer surgery.