<p>Down syndrome, also known as trisomy 21, is associated with an increased risk of respiratory morbidity disproportionate to the anatomical anomalies which accompany the disease. Intrinsic dysfunction of the airway epithelium plays a pivotal role in this vulnerability. This review examines three interrelated pathological mechanisms of epithelial barrier dysfunction in Down syndrome: tight junction defects, impaired mucus clearance, and dysregulated interferon driven epithelial-immune signaling. Studies using Down syndrome-specific air- liquid interface (ALI) cultures show delayed tight junction reassembly, reduced expression of proteins like ZO-1 and occludin, and increased epithelial permeability following viral exposure. Histological analyses also reveal goblet-cell hyperplasia, reduced multiciliated cells, and altered ion transport which together compromise mucus clearance. Triplication of interferon genes, IFNAR1/2, IL10RB, located on chromosome 21 perpetuates JAK-STAT signaling and heightens epithelium susceptibility to chronic inflammation. These defects fuel a pathologic loop of barrier permeability, abnormal infection signaling, and heightened inflammation contributing to long-term lung injury. This review synthesizes the literature on epithelial barrier dysfunction in Down syndrome and proposes an integrated pathophysiological model linking epithelial instability to immune amplification. Targeted therapies aim at strengthening the epithelial barrier, restoring mucociliary function and modulating hyperactive immune signaling offers promising treatments for Down syndrome-specific respiratory interventions. Where direct Down syndrome–specific experimental data are limited, mechanistic interpretations are presented as hypothesis-generating rather than definitive conclusions derived from non-DS pulmonary models.</p>