Class II malocclusion, particularly class II division 1, poses a significant orthodontic challenge with implications for both aesthetics and health. This study aimed to explore the impact of twin-block (TB) combined with maxillary expansion treatment (TB-ME) on upper airway dimensions and inflammatory profiles in adolescents with skeletal Class II Division 1 malocclusion in adolescent. Ninety-two eligible patients were randomly assigned to two groups: TB-ME treatment and traditional McLaughlin Bennett Trevisi (MBT) straight-wire orthodontic treatment (Control). Cephalometric lateral X-ray scans were conducted before and after treatment to assess skeletal changes, including SNA, ANB, and SNB angles, which are essential to assess the anteroposterior relationships of the maxilla and mandible to the cranial base. We also measured the upper airway volumes and areas. Concentrations of inflammatory factors including intercellular adhesion molecule 1 (ICAM-1), matrix metallopeptidase 2 (MMP2), and interleukin 8 (IL-8) of gingival crevicular fluid analysis (GCF) were detected by enzyme-linked immunosorbent assay. TB-ME treatment induced significant improvement in cephalometric parameters, including a decrease in SNA and ANB angles and an increase in SNB angle. Upper airway volumes and areas increased significantly in both groups, with TB-ME showing greater improvements. GCF analysis revealed a reduction in ICAM-1, MMP2, and IL-8 concentrations in the TB-ME group compared to the Control group. TB-ME treatment demonstrates multifaceted improvements in skeletal malocclusion, upper airway dimensions, and inflammatory profiles in adolescents with class II division 1 malocclusion, showing the promise of TB-ME in addressing the complexities associated with class II malocclusion.