Objective To explore the effect of gender on the median effective dose (ED50) of ciprofol under subanesthetic esketamine for gastroenteroscopy. Methods A total of 77 patients aged 18‒65 years old were enrolled and divided into three groups: group H (n=25, no gender restrictions), group M (n=24, all male), and group W (n=28, all female). According to Dixon's modified sequential method, esketamine 0.2 mg/kg was slowly administered to each patient during anesthesia induction, and then ciprofol was administered 30 s after injection. The initial dose of ciprofol was set at 0.4 mg/kg and the dose gradient was 0.05 mg/kg, and the dosage of ciprofol in the next patient was determined by Dixon's modified sequential method. Probit regression analysis was used to analyze the ED50, 95% effective dose (ED95), and 95% confidence interval (CI) of subanesthetic dose of esketamine and ciprofol for gastroenteroscopy in 3 groups. Mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) before anesthesia induction (T0) and after administration (T1) were recorded and perioperative anesthesia‑related adverse reactions were recorded. Results The ED50 and 95%CI of ciprofol under subanesthetic doses of esketamine for gastroenteroscopy were: group H was 0.349 (0.306~0.387) mg/kg, group M was 0.338 (0.262‒0.388) mg/kg while group W was 0.407 (0.363‒0.451) mg/kg. The ED95 and 95%CI were: group H was 0.427 (0.389‒0.655) mg/kg, group M was 0.439 (0.389‒0.903) mg/kg, and group W was 0.499 (0.454‒0.780) mg/kg. Compared with the group W, the ED50 and ED95 of ciprofol in group M were low (P<0.05). Compared with T0, SBP, DBP, MAP and heart rate in 3 groups decreased at T1 (all P<0.05). One patient in group W complained of dizziness, which was relieved after rest, and no obvious nausea, vomiting, or mental problems occurred in the three groups during the recovery period. Conclusions 0.2 mg/kg esketamine combined with ciprofol was stable in gastroenteroscopy, which was more suitable for gastroenteroscopy. Compared with males the ED50 and ED95 were increased by 20.41% and 13.67%, which could guide clinical use.