Objective To investigate of the application value of ciprofol combined with alfentanil in endoscopic submucosal dissection （ESD） of gastric masses. Methods Sixty patients who underwent gastric mass ESD from January 2023 to January 2024 were selected and randomly divided into a ciprofol anesthesia group （experimental group） and a propofol anesthesia group （control group） using a random number table method, with 30 patients in each group. In the control group, anesthesia was induced using 2 mg/kg propofol, 20 μg/kg alfentanil, and 0.15 mg cisatracurium, and maintained with 5 mg/（kg·h） propofol and 0.5 μg/（kg·min） alfentanil. In the experimental group, anesthesia was induced using 0.4 mg/kg ciprofol, 20 μg/kg alfentanil, and 0.15 mg/kg cisatracurium, and maintained with 1 mg/（kg·h） ciprofol and 0.5 μg/（kg·min） alfentanil. Comparisons were made between the two groups for hemodynamic indicators including non-invasive blood pressure （NIBP）, heart rate （HR）, oxygen saturation （SpO₂）, and partial pressure of end tidal carbon dioxide （PetCO₂）, surgical indicators （including extubation time, eye opening time, and agitation score）, and serum norepinephrine （NE） and cortisol （Cor） levels. Results At the time of entering the operation room （T0）, there was no significant difference in NIBP, HR, SpO₂, and PetCO₂ between the two groups （P>0.05）. After induction （T1）, at tracheal intubation （T2）, and after tracheal extubation （T3）, NIBP, HR, and SpO₂ decreased significantly while PetCO₂ increased, and compared with the control group, the experimental group had significantly higher NIBP, HR, and SpO₂ and significantly lower PetCO₂ （P<0.05）. When leaving the operation room （T4）, NIBP, HR, and SpO₂ increased, while PetCO₂ decreased, and the experimental group was better than the control group （P<0.05）. The extubation time, eye opening time, and agitation score of the experimental group were all lower than those of the control group （P<0.05）. There was no significant difference in the levels of NE and Cor at T0 between the two groups （P>0.05）, while the levels of NE and Cor at T1 and T4 increased significantly in both groups, and the levels of NE and Cor in the experimental group were lower than those in the control group （P<0.05）. Conclusion Compared with propofol combined with alfentanil, the combination of ciprofol and alfentanil in ESD surgery for gastric masses can effectively reduce hemodynamics, downregulate NE and Cor expression, shorten the time for extubation and eye opening, and alleviate patient agitation.