Lung epithelial lining fluid (ELF) harbors a variety of proteins that influence homeostatic and stress responses in the airspaces. Exosomes, nano-sized extracellular vesicles, contain a large number of proteins that vary in abundance and composition based on the prevailing conditions. Ozone causes inflammatory responses in the airspaces of experimental animals and humans. However, in ozone-exposed lung airspaces, the protein signatures in exosomes contained within the ELF remain poorly characterized. To explore this, we hypothesized that ozone triggers the release of inflammatory proteins from various cells that reflect ozone-induced tissue pathology. Accordingly, we sub-chronically exposed adult male and female mice to 0.8ppm ozone or air and determined exosome-bound proteomic signatures as well as the levels of soluble inflammatory mediators in the bronchoalveolar lavage fluid (BALF). Principal component analyses of the exosome-bound proteome revealed a clear distinction between air-exposed and ozone-exposed mice, as well as between ozone-exposed males and ozone-exposed females. In addition to 575 proteins that were enriched in both sexes upon ozone exposure, 243 and 326 proteins were enriched uniquely in ozone-exposed males and females, respectively. Ingenuity pathway analyses on enriched proteins between ozone- and air-exposed mice revealed enrichment of pro-inflammatory pathways. More specifically, macrophage-activation associated proteins were enriched in exosomes from ozone-exposed mice. Cytokine analyses on the BALF revealed elevated levels of G-CSF, MIP-1b, KC, IP-10, IL-6, and IL-5 in ozone-exposed mice. Finally, histopathological assessment revealed significantly enhanced intracellular localization of inflammatory proteins including MUC5B and FIZZ1 in ozone-exposed mice in cell-specific manner indicating the cellular sources of the proteins that are ferried in the exosomes upon ozone-induced lung injury. Collectively, this study identified exosomal, secretory, and cell-specific proteins and biological pathways following sub-chronic exposure of mice to ozone.