Traditional sedatives like Propofol can lead to adverse effects. This study compares the safety and efficacy of Ciprofol monotherapy versus combined Propofol for painless gastroscopy. Patients underwent painless gastroscopy at our hospital from January 2023 to December 2023 were studied. Sedation quality, adverse events, patient satisfaction, cognitive function, pain, anxiety, gastrointestinal side effects and endoscopic quality and so on was recorded and assessed. A retrospective analysis was conducted on patients undergoing painless gastroscopy from January to December 2023. Participants (n = 200) were categorized into Ciprofol (n = 102) and Combined Propofol (n = 98) groups. The Ciprofol group exhibited longer sedation onset (4.35 ± 1.71 min) but significantly quicker recovery (12.64 ± 4.54 min) compared to the combined group. Adverse events of nausea (2.94% vs 10.20%, p = 0.037) and vomiting (1.96% vs 9.18%, p = 0.025) were less frequent in the Ciprofol group, although satisfaction scores were similar between groups. Cognitive function, pain, anxiety levels and gastrointestinal side effects was comparable. Endoscopy quality measures showed no significant differences. Cyclophenol monotherapy is a viable alternative to combine Propofol, offering a reduced incidence of adverse effects and quicker recovery without compromising procedure quality or cognitive outcomes.