Objective To investigate the effectiveness and safety of esketamine at different doses in elderly patients undergoing gastrointestinal tumor operation. Methods A total of 120 patients aged 65 years or older who were scheduled for gastrointestinal tumor operation were selected. According to the random number table method, they were divided into four groups (n=30): a control group (group C), an esketamine 0.2 mg/kg group (group K1), an esketamine 0.3 mg/kg group (group K2), and an esketamine 0.4 mg/kg group (group K3). Then, patients in groups K1, K2 and K3 were administered with esketamine at 0.2, 0.3 mg/kg and 0.4 mg/kg for anesthesia induction, followed by intravenous infusion at a rate of 0.2, 0.3 mg·kg−1·h−1 and 0.4 mg·kg−1·h−1 for anesthesia maintenance. Meanwhile, those in C group were given the same volume of normal saline. The mean arterial pressure (MAP) and heart rate were recorded after the patients entering into the operation room (T0), 5 min after tracheal intubation (T1), 5 min after the beginning of the operation (T2), and at skin suture (T3). Furthermore, their consumption of sufentanil, norepinephrine and ephedrine, postoperative recovery time, extubation time, the Richmond Agitation‑Sedation Scale (RASS) score, the incidence of vertigo, nausea and vomiting, pruritus during postanesthesia care unit (PACU) stay and the Visual Analogue Scale (VAS) score when leaving PACU. Results Compared with those at T0, the four groups showed decreases in MAP at T1 (P<0.05), and heart rate at T2 (P<0.05). Compared with group C, groups K2 and K3 presented increased MAP at T1 (P<0.05), while group K3 showed increased MAP at T2 (P<0.05). There were no statistical differences in MAP and heart rate at other time points (P>0.05). The consumption of ephedrine in groups K1, K2 and K3 was lower than that in group C (P<0.05), and there was no statistical difference in the amount of sufentanil and norepinephrine among the four groups (P>0.05). Compared with group K3, the recovery time and extubation time of groups C, K1 and K2 were shortened (P<0.05). Compared with group C, group K showed increases in RASS score (P<0.05), while groups K2 and K3 presented decreases in the incidence of agitation (P<0.05). No adverse reactions such as nausea, vomiting, vertigo and pruritus occurred in the four groups, and there was no statistical difference in VAS pain score when leaving PACU (P>0.05). Conclusions For elderly patients undergoing gastrointestinal tumor operation, administration of esketamine at 0.3 mg/kg for anesthesia induction followed by intravenous infusion at a rate of 0.3 mg·kg−1·h−1 for anesthesia maintenance can improve hemodynamics, reduce the consumption of vasoactive agents, decrease the incidence of postoperative agitation and increase the clinical safety and effectiveness.