Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by recurrent upper airway collapse and chronic inflammation, leading to progressive airway remodeling. While nuclear factor-kappa B (NF-κB), a master regulator of inflammatory responses, is hypothesized to drive OSAHS-related pathology, its mechanistic role in hypoxia-and mechanical stress-induced upper airway inflammation remains poorly defined. In vitro and in vivo OSAHS models were established by exposing human airway epithelial cells (HBEpCs) and C57BL/6 mice to intermittent hypoxia (IH) or mechanical stretch. Experimental groups included IH-exposed models (IH group) and normoxic controls (Control/Sham group). To investigate therapeutic intervention, NF-κB was pharmacologically inhibited using BAY11-7082 (an IκBα phosphorylation inhibitor, BAY11-7082 group) versus vehicle controls (NC group). Pathological changes in murine upper airways (nasal turbinates and trachea) were assessed via hematoxylin-eosin and Masson staining. NF-κB activation (phospho-IκBα and nuclear p65) and infammatory markers (TNF-α, IL-6, IL-8) were quantified in murine tracheal tissues and HBEpCs using RT-qPCR and Western blot. Histological analysis revealed significant airway mucosal thickening in IH-exposed mice compared to controls (p < 0.01), which was attenuated by BAY11-7082 treatment (p < 0.05). Concurrently, IH exposure induced marked NF-κB activation (3.2-fold increase in phospho-IκBα, p < 0.01) and upregulation of pro-inflammatory cytokines (2.5-4.1-fold for TNF-α/IL-6, p < 0.05). Pharmacological NF-κB inhibition suppressed cytokine secretion by 60-75% in both cellular and murine models (p < 0.01). These findings were consistent across species, demonstrating that BAY11-7082 reversed IH-induced airway inflammation and structural remodeling. Our data establish NF-κB as a central mediator of upper airway inflammation in OSAHS, synergistically activated by intermittent hypoxia and mechanical stress. These results provide a mechanistic link between OSAHS pathophysiology and chronic inflammation, highlighting the therapeutic potential of NF-κB-targeted strategies.