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Abstract Introduction Nalbuphine has gradually become a commonly used clinical analgesic drug for painless hysteroscopy. The aim of our study was to identify the median effective dose (ED50) of propofol combined with nalbuphine for painless hysteroscopy. Methods Sixty-one patients aged 18–60 years were recruited to undergo elective painless hysteroscopy. Patients were administered 0.1 μg/kg nalbuphine (group A) or 0.2 μg/kg nalbuphine (group B) intravenously 3 min before endoscopic placement. The Dixon sequential method was used with an initial intravenous propofol dose of 2 mg/kg, which varied by 0.5 mg per kilogram. Results The ED50 of propofol was 1.729 mg/kg (95% confidence interval [CI] 1.526–1.856 mg/kg) in group A and 1.658 mg/kg (95% CI 1.359–1.799 mg/kg) in group B. The 95% effective dose (ED95) of propofol was 2.051 mg/kg (95% CI 1.899–3.331 mg/kg) in group A and 2.020 mg/kg (95% CI 1.849–3.832 mg/kg) in group B. Conclusion For safety and effective painless hysteroscopic, the ED50 values of propofol combined with nalbuphine were 1.729 mg/kg (0.1 mg/kg nalbuphine) and 1.658 mg/kg (0.2 mg/kg nalbuphine). The recommended dose of nalbuphine is therefore 0.1 mg/kg. Trial Registration Chinese Clinical Trial Registry: ChiCTR2100042342 ( http://www.chictr.org.cn/edit.aspx?pid=66342&htm=4 ; registration date 19 Jan 2021).