Respiratory Syncytial Virus (RSV) is a major respiratory pathogen implicated in the exacerbation of chronic lung diseases, including chronic obstructive pulmonary disease (COPD). Despite its increasing global burden, the mechanisms by which RSV contributes to disease development and progression remain poorly understood. To investigate the role of epithelial–fibroblast crosstalk in RSV-driven pathology, we established a well-differentiated primary airway epithelial cell (WD-PAEC) and fibroblast co-culture model to mimic the airway microenvironment. Using this system, we examined the differential host responses to RSV infection in healthy and COPD-derived cells across both single WD-PAEC and WD-PAEC–fibroblast co-cultures. Transcriptomic profiling revealed that RSV infection induced a greater number of differentially expressed genes in co-cultures compared with single cultures. Pathway analysis of single cultures highlighted responses related to infection, immune and inflammatory activation, and broad receptor signalling. In contrast, co-cultures exhibited pronounced enrichment of pathways associated with ciliary function, structural remodelling, and developmental signalling, including Hedgehog signalling which are key processes implicated in airway disease. Disease enrichment analysis using DisGeNET further distinguished the two models. While single cultures showed enrichment for generic inflammatory conditions, co-cultures displayed a transcriptional signature characteristic of respiratory disease and COPD exacerbation. Our data suggests the importance of epithelial-fibroblast interactions for studying respiratory disease and airway responses to RSV, highlighting the value of multicellular models for studying mechanisms underlying chronic lung disease.