Objective To investigate the effects of different fractions of inspired oxygen (FiO2) on the pulmonary oxygenation and respiratory mechanics in morbidly obese patients undergoing laparoscopic bariatric surgery. Methods A total of 99 morbidly obese patients who were scheduled for laparoscopic bariatric surgery were selected. According to the random number table method, they were divided into three groups and maintained the following treatment after intubation under general anesthesia until the end of surgery: FiO2 40% (group L, n=33), FiO2 60% (group M, n=33) and FiO2 80% (group H, n=33). Before oxygenation (T0), 5 min after reaching the target oxygen concentration (T1), 1 h after pneumoperitoneum (T4), 5 min after the end of pneumoperitoneum (T5), 10 min after entry into postanesthesia care unit (PACU) (T6) and discharge from PACU (T7), radial artery blood was collected to conduct blood gas analysis, and the oxygenation index (PaO2/FiO2), arterial/alveolar oxygen partial pressure ratio (a/APO2), and partial pressure of artery carbon dioxide (PaCO2) were recorded and calculated. The plateau pressure (Pplat), peak airway pressure (Ppeak), and pulmonary dynamic compliance (Cdyn) were recorded at T1, 5 min after pneumoperitoneum (T2), 30 min after pneumoperitoneum (T3), T4 and T5. The duration from drug withdrawal to extubation, the length of PACU stay, hyperoxia [partial pressure ofoxygen (PaO2)>300 mmHg during surgery, 1 mmHg=0.133 kPa] and oxygen desaturation events [percutaneous oxygen saturation (SpO2)<95% during surgery, the number and duration when SpO2 dropped to 92% within 5 min after extubation, and SpO2<92% during PACU], adverse events (nausea and vomiting in PACU, need to apply oropharyngeal airway or non‑invasive positive pressure ventilation), and the length of postoperative hospital stay were recorded. Results There were no significant differences in general data among the three groups (P>0.05). Compared with group M, the length of PACU stay prolonged in groups L and H (P<0.05), and there were no significant differences in other clinical characteristic data (P>0.05). Group H produced lower PaO2/FiO2 at T6‒T7 than groups L and M(P<0.05). Group H produced higher PaO2/FiO2 at T4, lower Cdyn at T5, and higher PaCO2 at T6 than group L (P<0.05). The incidence of hyperoxia in group H was higher than those in groups L and M (P<0.05). There were no significant differences in PaO2/FiO2 and PaCO2 at T0, T1, and T5, a/APO2 at T0, T1 and T4‒T7, Cdyn at T1‒T4, Pplat and Ppeak at T1‒T5 among the three groups (P>0.05). Compared with those at T0, decreased PaO2/FiO2 was found in the three groups at T1, T4, T6, T7 and in group L at T5, while decreased a/APO2 and increased PaCO2 were seen in the three groups at T1 and T4‒T7 (P<0.05). Compared with those at T6, there were no significant differences as to PaO2/FiO2, a/APO2, and PaCO2 in the three groups at T7 (P>0.05). Compared with those at T1, the three groups produced increased Pplat and Ppeak (P<0.05) and decreased Cdyn at T2‒T5 (P<0.05). Compared with those at T4, the three groups produced decreased Pplat and Ppeak (P<0.05) and increased Cdyn at T5 (P<0.05). There were no significant differences in oxygen desaturation and adverse events among the three groups (P>0.05). Conclusions Compared with 40% and 80% FiO2, ventilation with 60% FiO2 is effective in optimizing the pulmonary oxygenation and respiratory mechanics in morbidly obese patients undergoing laparoscopic bariatric surgery, reduce the incidence of hyperoxemia without increasing the risk of oxygen desaturation and adverse events.