Objective To investigate the risk factors associated with hypoxemia after extubation in neonates with Pierre Robin sequence (PRS) undergoing mandibular distraction osteogenesis (MDO). Methods A total of 84 PRS neonates who underwent MDO in Peking University International Hospital from January 2016 to October 2021 were enrolled and their clinical data were retrospectively analyzed. According to the presence of hypoxemia after extubation [medical intervention at pulse oxygen saturation (SpO2)<90%], they were divided into two groups: a hypoxemia group (n=50) and a non‑hypoxemia group (n=34). The medical interventions of the hypoxemia group were recorded. Logistic regression analysis was utilized to establish a predictive mode to identify the independent risk factors related to hypoxemia. Results There were 50 babies (59.5%) who developed hypoxemia after extubation. Medical interventions included changing posture in 38 neonates (45.2%), placing a nasopharyngeal airway in 8 children (9.5%) and placing a laryngeal mask for mechanical ventilation in 4 children (4.8%). Multivariate logistic regression showed the independent risk factors of hypoxemia were lower‑body weight [odds ratio (OR) 1.263, [95% confidence interval (CI) 1.024, 2.361], P=0.002] and shorter extubation time [OR 0.331 (95%CI 0.247, 0.764), P=0.043]. Conclusions Lower‑body weight is an independent risk factor for hypoxemia after extubation in PRS neonates undergoing MDO, and babies with shorter extubation time is a higher incidence of hypoxemia.