Objective To investigate the safety of painless colonoscopy in the treatment of obese patients during high‑flow nasal cannula oxygen therapy. Methods A total of 100 obese patients, ASA Ⅰ−Ⅲ, BMI≥28 kg/m2, who underwent painless colonoscopy in the First Affiliated Hospital of Xi'an Jiaotong University were selected. According to the random number table method, the patients were divided into two groups (n=50): an experimental group (group H, who received high‑flow nasal cannula oxygen therapy, at an oxygen flow of 20−60 L/min) and a control group (group C, who underwent conventional oxygen inhalation via nasal catheter, at an oxygen flow of 3−5 L/min). Then, their mean arterial pressure (MAP), heart rate and saturation of pulse oximetry (SpO2) at T0 (immediately after entry into operation room), T1 (1 min after colonoscope insertion)， T2 (when insertion of the tip of the colonoscope into the terminal ileum) and T3 (immediately before hospital discharge) were recorded. Furthermore, the incidence of emergency management, the total dosage of propofol, the length of colonoscopy procedure, the awakening time, adverse reactions, and the satisfaction of endoscopists and patients were also recorded. Results There was no significant difference between group H and group C in general condition, the incidence of adverse reactions, the total dosage of propofol, the length of endoscopic examination and recovery time (P>0.05). Group H produced remarkable increases in SpO2 at T1 compared with group C (P<0.05). There were 11 cases (22%) of emergency treatment for group H, which were significantly lower than 33 cases (66%) in group C (P<0.05). The satisfaction of both endoscopists and patients from group H was significantly higher than that of group C (P<0.05). Conclusions High‑flow nasal cannula oxygen therapy can improve the safety of painless colonoscopy examination in obese patients.