The COVID-19 pandemic has revealed differences in individual susceptibility and severity, with pre-existing respiratory diseases as potential risk factors. Using an in vitro model of differentiated primary bronchial epithelial cells, we investigated the molecular mechanisms of SARS-CoV-2 infection in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Our study found that CF and COPD airway epithelium had reduced susceptibility to SARS-CoV-2 compared to healthy controls. This was linked to preserved epithelial integrity, lower viral replication, and attenuated antiviral and inflammatory responses. Mechanistically, we identified reduced TMPRSS2 activity as a contributing factor in CF epithelium. Importantly, the baseline upregulation of complement and inflammatory pathways in CF and COPD epithelium appeared to prime an antiviral state prior to infection. Analysis of a COVID-19 patient cohort validated our findings, showing correlations between specific inflammatory markers (CXCL-10, SERPINA1, and CFB) and SARS-CoV-2 infection severity. This study offers insights into SARS-CoV-2 pathogenesis and potential biomarkers for clinical monitoring.