In this study, we developed a 3D lung model that incorporated alveolar and vascular components, allowing for the investigation of lung physiology and responses to infection. We investigated the role of ventilation in formation of the alveolar epithelial layer and its response to viral infections. We subjected our perfused model to a continuous respiratory cycle at the air-liquid interface (ALI) for up to 10 days. The results revealed that ventilation increased tight-junction formation with better epithelial barrier function over time. Two viruses, influenza and respiratory syncytial virus (RSV), were tested, where ventilation enhanced infectivity with an increased progression of viral spread over time while sensitizing the epithelium for viral recognition. Ventilation also attenuated the production of key proinflammatory chemokines. Our findings represent a critical step forward in advancing our understanding of lung-specific viral responses and respiratory infections in response to ventilation, shedding light on vital aspects of pulmonary physiology and pathobiology.