Objective To investigate the effectiveness and safety of low dose esketamine combined with ciprofol infusion in elderly patients undergoing endoscopic submucosal dissection (ESD). Methods 60 patients with endoscopic colorectal ESD, aged 65-75 years, BMI18-28kg/m2, ASA grade I-III, were selected. Patients were divided into two groups according to random number table method: esketamine group (group E) and remifentanil group (group R). Group E was given 0.1mg/kg esketamine and ciprofol 0.4 mg/kg for anesthesia onset, group R was given 0.4 μg/kg remifentani and ciprofol 0.4 mg/kg for anesthesia onset. Anesthesia maintenance was administered with esketamine 0.1-0.2 mg·kg-1·h-1 and ciprofol 0.8-1mg·kg-1·h-1 in group E, while anesthesia was maintained with remifentanil 0.05~0.1mg·kg-1·min-1 and ciprofol 0.8-1mg·kg-1·h-1 in group R. The induction time, awakening time, departure time and surgical time were recorded. The dosage of ciprofol and cases of using vasoactive drugs were recorded. The occurrence of intraoperative and postoperative adverse events were recorded. HR, MAP, SpO2, RR, IoC1 and IoC2 were recorded before anesthesia (T0), 1min after induction (T1), colonoscopy implantation (T2), submucosal dissection (T3), wound treatment (T4), and recovery (T5). The VAS score of 15min/2hours/4hours/24hous after surgery, satisfaction of anesthesiologist, endoscopist and patient were recorded. Results Compared with group R, the incidence of intraoperative hypotension and respiratory depression was decreased in group E, dosages of norepinephrine and ephedrine were decreased (P0.05), MAP, RR and SpO2 were higher (P0.05), and endoscopists' satisfaction was higher (P0.05). There were no significant differences between the two groups in the incidence of intraoperative bradycardia and motor incidence, dosage of ciprofol and atropine, intraoperative HR,BIS,IoC1 and IoC2 incidence of postoperative adverse reactions (P0.05). Conclusions Low-dose esketamine combined with ciprofol infusion is safe and effective for elderly patients undergoing ESD, while the hemodynamic fluctuation and respiratory depression is less with higher satisfaction score of endoscopist.