Abstract: Objective To evaluate the safety and effectiveness of remimazolam combined with nalbuphine for painless colonoscopy in obese patients. Methods Ninety obese patients who underwent painless colonoscopy at the Second Affiliated Hospital of Xuzhou Medical University from February to July 2024 were selected. They were randomly divided into two groups (n=45): propofol combined with nalbuphine (group PN) and remimazolam combined with nalbuphine (group RN). The mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SpO₂) were recorded before anesthesia (T1), at the time the endoscope entered the anus (T2), at the time the endoscope reached the hepatic flexure (T3), at the time the endoscope reached the cecum (T4), and at the end of the examination (T5). The onset time of anesthesia, colonoscopy duration, emergence time, and the length of PACU stay were recorded. Furthermore, the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score, Behavioral Pain Scale-Non Intubated (BPS-NI) score >5, adverse reactions, and patient satisfaction were recorded. The postoperative recovery quality was assessed using the QoR-15 scale. Results The incidence of hypoxemia in group RN (11.11%) was lower than in group PN (37.78%) (P<0.05). From T2 to T5, the SpO₂ and MAP of group RN were significantly higher than those of group PN (P<0.05). Compared with group PN, group RN showed significantly reduced emergence time and shortened length of PACU stay (P<0.001), with decreased incidences of severe hypoxemia, hypotension, dizziness, and injection pain (P<0.05). There were no significant differences between the two groups in terms of MOAA/S score and BPS-NI >5 score (P>0.05). The postoperative QoR-15 score and patient satisfaction in group RN were higher than those in group PN (P<0.05). Conclusions Compared with propofol-nalbuphine, remimazolam-nalbuphine combination demonstrates superior safety and effectiveness for colonoscopy in obese patients, with shortened emergence time, reduced adverse events, and improved postoperative recovery quality.