Objective To investigate the effectiveness and safety of different doses of intranasal esketamine for reducing preoperative anxiety in preschool children. Methods A total of 90 children, aged 2 to 6 years old, who were scheduled for interventional cardiac catheterisation were included in the current study. According to the random number table method, they were divided into three groups (n=3): an esketamine 0.5 mg/kg group (group S1), an esketamine 1.0 mg/kg group (group S2) and an esketamine 1.5 mg/kg group (group S3). The children were administered with the corresponding dosage of intranasal esketamine in the ward, and then transferred to the operating room 30 min later. The modified Yale Preoperative Anxiety Scale⁃Short Form (mYPAS⁃SF) was used to evaluate children's anxiety at the following time points: before nasal drip (T0), 15 min after nasal drip (T1), and 30 min after nasal drip (T2). Meanwhile, the heart rate, mean artery pressure (MAP) and oxygen saturation (SpO2) were recorded. The level of sedation, the satisfaction of separation emotion and the satisfaction of mask cooperation were evaluated using the corresponding scales (Ramsay scores, ease of separation and ease of induction score), and the incidence of adverse reactions within 24 h after operation was recorded. Results Compared with group S1, the mYPAS⁃SF of group S2 and group S3 at T1 and T2 was reduced (P<0.05). Compared with T0, mYPAS‑SF decreased at T1 and T2 in the three groups (P<0.05). Compared with those at T1, mYPAS‑SF increased at T2 in the three groups (P<0.05). There was no significant difference in mYPAS⁃SF among the three groups at T0 (P>0.05). There was no significant difference in mYPAS⁃SF between group S2 and group S3 at each time point (P>0.05). The satisfaction rates of separation emotion and mask cooperation in both group S2 and group S3 were higher than those in group S1 (P<0.05). There was no significant difference in the success rate of sedation among the three groups (P>0.05). The incidences of postoperative nausea, vomiting and irritability in group S3 were higher than those in the other two groups, without statistical differences (P>0.05). Conclusions Intranasal esketamine at 1.0 mg/kg can relieve the preoperative anxiety of preschool children, which is equivalent to intranasal esketamine at 1.5 mg/kg but reduces the incidence of postoperative adverse reactions.