Objective To investigate the anesthetic efficacy, effects on respiratory function, and safety evaluation of oliceridine combined with ciprofol in patients undergoing gastrointestinal endoscopy.Methods A total of 120 patients who underwent painless gastrointestinal endoscopy in Sichuan Friendship Hospital from April 2025 to September 2025 were included and randomly divided into a control group and an observation group, with 60 patients in each group. The control group received a combination of ciprofol (0.4 mg/kg) and sufentanil (0.1 μg/kg), while the observation group received a combination of ciprofol (0.4 mg/kg) and oliceridine (0.02 mg/kg). The anesthetic effects (onset time, recovery time, and time to discharge from the endoscopy unit), hemodynamic parameters [mean arterial pressure (MAP) and heart rate (HR) ] and oxygen saturation (SpO₂) before sedation (T₁), during passage of the gastroscope through the pharynx (T₂), during passage of the colonoscope through the anus (T₃), during passage of the colonoscope through the hepatic flexure (T₄), and at the end of the examination (T₅), and adverse reactions (including coughing, body movement responses, respiratory depression, nausea, vomiting, injection pain, etc.) were compared between the two groups.Results The recovery time and time to discharge from the endoscopy unit were shorter in the observation group than in the control group (P < 0.05). Comparisons of MAP and HR between the observation and control groups at T₁, T₂, T₃, T₄, and T₅ showed that significant differences were observed in MAP and HR among different time points (P < 0.05) and between the two groups (P < 0.05), and that significant differences were observed in the trends of MAP and HR changes between the two groups (P < 0.05). Comparisons of SpO₂ between the two groups at T₁, T₂, T₃, T₄, and T₅ showed that significant differences were observed in SpO₂ among different time points (P < 0.05) and between the observation and control groups (P < 0.05), and that significant differences were observed in the trends of SpO₂ changes between the two groups (P < 0.05). No significant differences were found between the two groups in the incidence of injection pain or nausea and vomiting (P > 0.05). The incidences of coughing, body movement responses, and respiratory depression were lower in the observation group than in the control group (P < 0.05).Conclusion Oliceridine combined with ciprofol for painless gastrointestinal endoscopy sedation can accelerate recovery and discharge, maintain hemodynamic stability, reduce respiratory depression, and decrease nausea and vomiting reactions, demonstrating favorable efficacy and safety.