Introduction: Mandibular setback surgery (MSS) is one of the treatment options to resolve mandibular prognathism in patients suffering from skeletal class III malocclusion, which cannot be treated with simple orthodontic treatment. The mandibular setback surgical operation can involve changes in the pharyngeal morphology, resulting in a narrowing of the posterior airway space (PAS). This aspect is associated with an increase in airflow resistance, which increases the risk of developing snoring or obstructive sleep apnea syndrome (OSAS). The aim of this study is to evaluate the medium- and long-term effects of mandibular setback surgery on the upper airways and its possible association with OSAS in patients suffering from class III skeletal malocclusion. Material and methods: A total of 12 patients (5 males and 7 females) were enrolled in this study. The statistical tests highlighted a significant change in the PAS and BMI values in relation to T0, before surgery (PAS: 12.7 SD: 1.2; BMI: 21.7 SD: 1.2), and T1, after surgery (PAS: 10.3 SD: 0.6, p < 0.01; BMI: 23.8 SD: 1.2, p < 0.05). Sample size was calculated to detect an effect size of 0.9, with statistical power set at 0.8 and the significance level set at 0.05. Results: No statistically significant correlation was found between the extent of mandibular setback, PAS and BMI change. Conclusion: This study confirms the effects of mandibular setback surgery on the upper airways, reporting a statistically significant PAS reduction in the medium- and long-term follow-up. On the other hand, no direct correlation was identified with OSAS risk, at least for the small mandibular setback (<8 mm), despite the statistically significant increase in BMI.