Human rhinoviruses have been identified as the primary etiologic agent of the common cold since the 1950s, yet over 65 years later there is no cure for rhinovirus infections. Rhinoviruses are extremely well adapted respiratory viruses that establish infections without causing overt cytotoxicity to their natural host cells, airway epithelial cells, which undergo extensive phenotypic changes during infection. These changes range from viral recognition to release of host defense molecules to physical changes in epithelial cytoskeletal architecture. As a mucosal surface, the airway epithelium primarily serves to maintain a tight epithelial barrier and perform immunosurveillance for invading pathogens. Therefore, the majority of our understanding of HRV infections focuses on host defense molecule regulation, and innate viral-specific host defense responses. However, our understanding of airway epithelial host defense remains incomplete, particularly the mechanisms by which the airway epithelium maintains both barrier function and metabolic processes during bioenergetically demanding events such as rhinovirus infections. In this work, we use a physiologically relevant in vitro modeling system, air-liquid interface (ALI) cultures of highly differentiated human bronchial epithelial cells, to effectively model rhinovirus-epithelial interactions to investigate two understudied epithelial functions during infection: epithelial barrier function and metabolism. There is a spectrum of barrier loss severity that occurs during rhinovirus infection and early-onset paracellular permeability is marked by changing cytoskeletal signaling pathways regulating actin stabilization and contractile mechanisms associated with tight junction integrity. Metabolomics and proteomics revealed that changing cell metabolism was a prominent feature of rhinovirus infections and allowed for the identification of a master regulator of cellular bioenergetics, peroxisome proliferator-activated receptor-gamma coactivator 1a (PGC-1a), as not only a metabolic regulator, but regulator of airway epithelial barrier function. Pharmacological promotion of PGC-1a resulted in restoration of rhinovirus-induced barrier loss, reduction in viral replication, and enhancement of antiviral host defenses. PGC-1a was further implicated in interacting with low energy sensing signaling pathways to promote enhanced interferon and antiviral host defenses during rhinovirus infection. This investigation strives to form a more unifying understanding of airway epithelial host defense responses of barrier function, metabolism, and antiviral responses to rhinovirus infections.